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The Journal of STEM Education: Innovations and Research is a quarterly, peer-reviewed publication for educators in Science, Technology, Engineering, and Mathematics (STEM) education. The journal emphasizes real-world case studies that focus on issues that are relevant and important to STEM practitioners. These studies may showcase field research as well as secondary-sourced cases. The journal encourages case studies that cut across the different STEM areas and that cover non-technical issues such as finance, cost, management, risk, safety, etc. Case studies are typically framed around problems and issues facing a decision maker in an organization.

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Stem vs. steam education and student creativity: a systematic literature review.

1. Introduction

• Through which STEM/STEAM conceptual approach were the didactic interventions prepared that are used to develop student creativity?
• From which perspective was creativity evaluated, and which instruments were employed to do so?
• What reasons do the authors identify to explain the effect of interventions based on STEM/STEAM approach on creativity?

1.1. Conceptual Approach toward STE(A)M Education

• Its focus is ihe resolution of problems based on concepts and procedures from science and mathematics, which incorporate the strategies applied in engineering and the use of technology [ 12 ].
• It is an E–A approach that integrates two or more STEM areas and/or one or more curricular subjects [ 10 ].
• It is an approach that seeks to teach content from two or more STEM domains, framed within a real context, so as to connect the subject matter with the daily life of the student [ 13 ].
• It is a meta-discipline based on learning standards where the teaching has an integrated approach; the specific content of this discipline is not divided; and it uses dynamic and fluid instruction methods [ 14 ], a perspective that is also found in Zollman [ 15 ].
• Yakman and Lee [ 18 ] defined STEAM education as the interpretation of science and technology through engineering and the arts (a century that covered the humanities was studied); all based on mathematical elements.
• Zamorano et al. [ 19 ] defined STEAM as the interdisciplinary integration of sciences, technology, engineering, the arts and mathematics for the resolution of the daily life problems of students.

1.2. Creativity and Its Development in the Workshop

• Mini-c or interpretative creativity (e.g., when a student solves a mathematical problem in a different way to the example given in class).
• Little-c or daily creativity (e.g., development of a local project to solve an overabundance of pine processionary caterpillars).
• Pro-C or creativity expert (e.g., the idea of the inverted classroom that Aaron Sams and Jonathan Bergmann, both teachers, have advanced).
• Big-C or legendary creativity (e.g., the educational approach that Maria Montessori first devised).

2.1. Article Selection Procedure

• Journal articles or congress communications (proceedings) written in either Spanish or English.
• The terms “STEM/STEAM education” and “creativity” appear in the title, abstract or keywords.
• They present an educational intervention embedded in formal education in which the development of the creativity of students is considered.
• They use research instruments to evaluate the creativity of the participants.
• They set out conclusions on the impact of STEM or STEAM education on creativity.

2.2. Data Extraction Procedure

2.3. description of the articles under analysis, 3. results and discussion, 3.1. conceptualizations of the stem and steam approaches.

“EarSketch is an integrated STEAM programming environment and curriculum that teaches elements of computing and sample-based music composition (i.e., composition using musical beats, samples, and effects) in an effort to engage a diverse population of students. […] EarSketch fosters a learning environment that is both personally meaningful and of industrial relevance in terms of its STEM component (computing) and its artistic domain (music remixing).” [ 41 ] (p. 183)

“The Creations project was set up to overcome this development. In Creations, a project funded by the European Union, 16 partners from ten European countries developed creative approaches based on art for an engaging science classroom. It breaks new ground to increase young people’s interest in science, particularly by supporting the link between science and creativity.” [ 49 ] (p. 4)

“Thus, this study adopted a science and art-based approach by teaching the science topics. The technology was accessed through the use of tablet computers. Tablet computers are among the multi-sensory tools employed in STEAM education. The add-on applications on the tablet computer screen or tactile display stimulates sensory interaction (Taljaard 2016). The engineering field includes the design process (Charyton 2015). The mathematics field is included in the calculations of the STEAM design.” [ 46 ] (p. 11)

3.2. Type of Creativity Evaluated and Instruments Employed

• The process. This is attending to the creative process or, what is the same, to the procedures (actions) that the individual develops.
• The context. Environmental factors that act as promoters or limiters of creativity are evaluated.
• Person. The creativity capacity of the individual (cognitive abilities and perceptions of his creative skills) is assessed using test or questionnaires.
• The product. Attention is paid to those characteristics of the results obtained (an essay, a drawing, a model, …) that show originality and creative potential.

3.3. Effect of the STE(A)M Interventions on Creativity

4. conclusions.

• Neither the STEM nor the STEAM educational approach enjoys the conceptual clarity for researchers, academics and/or teachers to design, implement and evaluate didactic interventions based on those educational approaches with a certain degree of similarity, in so far as the didactic and pedagogical principles are concerned (for example, the number of disciplines that they should integrate or the way they should be integrated).
• Both the STEM and the STEAM educational interventions are centered on the creativity of the person, on the whole using Likert-type questionnaires. Nevertheless, STEAM education appears to lend greater attention to the context in which the E–A process was developed, whereas STEM education was proven to be of a more finalist nature, by centering the analysis on the products created by the students.
• Both STEM and STEAM education generated positive effects on student creativity. However, the references upon which we relied in this review were too few and far between for us to certify with some rigor that the bonds of these educational approaches can promote the potential development of creativity within the student. Despite this lack of clarity, although the convenience of STEAM education, over and above STEM education, might appear clear, with a view to developing the creativity of students [ 5 , 52 , 56 ], it is an invalid argument.

Author Contributions

Conflicts of interest.

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Aguilera, D.; Ortiz-Revilla, J. STEM vs. STEAM Education and Student Creativity: A Systematic Literature Review. Educ. Sci. 2021 , 11 , 331. https://doi.org/10.3390/educsci11070331

Aguilera D, Ortiz-Revilla J. STEM vs. STEAM Education and Student Creativity: A Systematic Literature Review. Education Sciences . 2021; 11(7):331. https://doi.org/10.3390/educsci11070331

Aguilera, David, and Jairo Ortiz-Revilla. 2021. "STEM vs. STEAM Education and Student Creativity: A Systematic Literature Review" Education Sciences 11, no. 7: 331. https://doi.org/10.3390/educsci11070331

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• Published: 26 February 2019

Stem cells: past, present, and future

• Wojciech Zakrzewski 1 ,
• Maciej Dobrzyński 2 ,
• Maria Szymonowicz 1 &
• Zbigniew Rybak 1  

Stem Cell Research & Therapy volume  10 , Article number:  68 ( 2019 ) Cite this article

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In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Stem cell classification

Stem cells are unspecialized cells of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. There are several steps of specialization. Developmental potency is reduced with each step, which means that a unipotent stem cell is not able to differentiate into as many types of cells as a pluripotent one. This chapter will focus on stem cell classification to make it easier for the reader to comprehend the following chapters.

Totipotent stem cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential and allows cells to form both embryo and extra-embryonic structures. One example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. These cells can later develop either into any of the three germ layers or form a placenta. After approximately 4 days, the blastocyst’s inner cell mass becomes pluripotent. This structure is the source of pluripotent cells.

Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta. Embryonic stem cells (ESCs) are an example. ESCs are derived from the inner cell mass of preimplantation embryos. Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. Their pluripotency is a continuum, starting from completely pluripotent cells such as ESCs and iPSCs and ending on representatives with less potency—multi-, oligo- or unipotent cells. One of the methods to assess their activity and spectrum is the teratoma formation assay. iPSCs are artificially generated from somatic cells, and they function similarly to PSCs. Their culturing and utilization are very promising for present and future regenerative medicine.

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages. One example is a haematopoietic stem cell, which can develop into several types of blood cells. After differentiation, a haematopoietic stem cell becomes an oligopotent cell. Its differentiation abilities are then restricted to cells of its lineage. However, some multipotent cells are capable of conversion into unrelated cell types, which suggests naming them pluripotent cells.

Oligopotent stem cells can differentiate into several cell types. A myeloid stem cell is an example that can divide into white blood cells but not red blood cells.

Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type, e.g. dermatocytes.

Stem cell biology

A blastocyst is formed after the fusion of sperm and ovum fertilization. Its inner wall is lined with short-lived stem cells, namely, embryonic stem cells. Blastocysts are composed of two distinct cell types: the inner cell mass (ICM), which develops into epiblasts and induces the development of a foetus, and the trophectoderm (TE). Blastocysts are responsible for the regulation of the ICM microenvironment. The TE continues to develop and forms the extraembryonic support structures needed for the successful origin of the embryo, such as the placenta. As the TE begins to form a specialized support structure, the ICM cells remain undifferentiated, fully pluripotent and proliferative [ 1 ]. The pluripotency of stem cells allows them to form any cell of the organism. Human embryonic stem cells (hESCs) are derived from the ICM. During the process of embryogenesis, cells form aggregations called germ layers: endoderm, mesoderm and ectoderm (Fig.  1 ), each eventually giving rise to differentiated cells and tissues of the foetus and, later on, the adult organism [ 2 ]. After hESCs differentiate into one of the germ layers, they become multipotent stem cells, whose potency is limited to only the cells of the germ layer. This process is short in human development. After that, pluripotent stem cells occur all over the organism as undifferentiated cells, and their key abilities are proliferation by the formation of the next generation of stem cells and differentiation into specialized cells under certain physiological conditions.

Oocyte development and formation of stem cells: the blastocoel, which is formed from oocytes, consists of embryonic stem cells that later differentiate into mesodermal, ectodermal, or endodermal cells. Blastocoel develops into the gastrula

Signals that influence the stem cell specialization process can be divided into external, such as physical contact between cells or chemical secretion by surrounding tissue, and internal, which are signals controlled by genes in DNA.

Stem cells also act as internal repair systems of the body. The replenishment and formation of new cells are unlimited as long as an organism is alive. Stem cell activity depends on the organ in which they are in; for example, in bone marrow, their division is constant, although in organs such as the pancreas, division only occurs under special physiological conditions.

Stem cell functional division

Whole-body development.

During division, the presence of different stem cells depends on organism development. Somatic stem cell ESCs can be distinguished. Although the derivation of ESCs without separation from the TE is possible, such a combination has growth limits. Because proliferating actions are limited, co-culture of these is usually avoided.

ESCs are derived from the inner cell mass of the blastocyst, which is a stage of pre-implantation embryo ca. 4 days after fertilization. After that, these cells are placed in a culture dish filled with culture medium. Passage is an inefficient but popular process of sub-culturing cells to other dishes. These cells can be described as pluripotent because they are able to eventually differentiate into every cell type in the organism. Since the beginning of their studies, there have been ethical restrictions connected to the medical use of ESCs in therapies. Most embryonic stem cells are developed from eggs that have been fertilized in an in vitro clinic, not from eggs fertilized in vivo.

Somatic or adult stem cells are undifferentiated and found among differentiated cells in the whole body after development. The function of these cells is to enable the healing, growth, and replacement of cells that are lost each day. These cells have a restricted range of differentiation options. Among many types, there are the following:

Mesenchymal stem cells are present in many tissues. In bone marrow, these cells differentiate mainly into the bone, cartilage, and fat cells. As stem cells, they are an exception because they act pluripotently and can specialize in the cells of any germ layer.

Neural cells give rise to nerve cells and their supporting cells—oligodendrocytes and astrocytes.

Haematopoietic stem cells form all kinds of blood cells: red, white, and platelets.

Skin stem cells form, for example, keratinocytes, which form a protective layer of skin.

The proliferation time of somatic stem cells is longer than that of ESCs. It is possible to reprogram adult stem cells back to their pluripotent state. This can be performed by transferring the adult nucleus into the cytoplasm of an oocyte or by fusion with the pluripotent cell. The same technique was used during cloning of the famous Dolly sheep.

hESCs are involved in whole-body development. They can differentiate into pluripotent, totipotent, multipotent, and unipotent cells (Fig.  2 ) [ 2 ].

Changes in the potency of stem cells in human body development. Potency ranges from pluripotent cells of the blastocyst to unipotent cells of a specific tissue in a human body such as the skin, CNS, or bone marrow. Reversed pluripotency can be achieved by the formation of induced pluripotent stem cells using either octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), or the Myc gene

Pluripotent cells can be named totipotent if they can additionally form extraembryonic tissues of the embryo. Multipotent cells are restricted in differentiating to each cell type of given tissue. When tissue contains only one lineage of cells, stem cells that form them are called either called oligo- or unipotent.

iPSC quality control and recognition by morphological differences

The comparability of stem cell lines from different individuals is needed for iPSC lines to be used in therapeutics [ 3 ]. Among critical quality procedures, the following can be distinguished:

Short tandem repeat analysis—This is the comparison of specific loci on the DNA of the samples. It is used in measuring an exact number of repeating units. One unit consists of 2 to 13 nucleotides repeating many times on the DNA strand. A polymerase chain reaction is used to check the lengths of short tandem repeats. The genotyping procedure of source tissue, cells, and iPSC seed and master cell banks is recommended.

Identity analysis—The unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testing—An appearance of reprogramming vectors integrated into the host genome is hazardous, and testing their presence is a mandatory procedure. It is a commonly used procedure for generating high-quality iPSC lines. An acceptable threshold in high-quality research-grade iPSC line collections is ≤ 1 plasmid copies per 100 cells. During the procedure, 2 different regions, common to all plasmids, should be used as specific targets, such as EBNA and CAG sequences [ 3 ]. To accurately represent the test reactions, a standard curve needs to be prepared in a carrier of gDNA from a well-characterized hPSC line. For calculations of plasmid copies per cell, it is crucial to incorporate internal reference gDNA sequences to allow the quantification of, for example, ribonuclease P (RNaseP) or human telomerase reverse transcriptase (hTERT).

Karyotype—A long-term culture of hESCs can accumulate culture-driven mutations [ 4 ]. Because of that, it is crucial to pay additional attention to genomic integrity. Karyotype tests can be performed by resuscitating representative aliquots and culturing them for 48–72 h before harvesting cells for karyotypic analysis. If abnormalities are found within the first 20 karyotypes, the analysis must be repeated on a fresh sample. When this situation is repeated, the line is evaluated as abnormal. Repeated abnormalities must be recorded. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism (SNP) array, discussed later, has approximately 50 times higher resolution.

Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed (e.g. hepatitis C or human immunodeficiency virus). This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.

Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide (ASO) probes. The last component detects, records, and eventually interprets the signal.

Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample.

Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image. Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].

Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.

hESC derivation and media

hESCs can be derived using a variety of methods, from classic culturing to laser-assisted methodologies or microsurgery [ 11 ]. hESC differentiation must be specified to avoid teratoma formation (see Fig.  3 ).

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals (in forms of soluble factors and culture conditions) are applied and enable the selection of progenitor cells

hESCs spontaneously differentiate into embryonic bodies (EBs) [ 12 ]. EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ].

The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs (Fig.  4 ) [ 17 ]. Rosowski et al. [ 18 ] emphasizes that particular attention must be taken in controlling spontaneous differentiation. When the colony reaches the appropriate size, cells must be separated. The occurrence of pluripotent cells lasts for 1–2 days. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. [ 19 ] found out that it is also possible to obtain hESCs from four cell embryos, leaving a higher probability of embryo survival. Additionally, Zhang et al. [ 20 ] used only in vitro fertilization growth-arrested cells.

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures.

Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ].

Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice (GMP)-grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase (ROCK) [ 26 ].

Ethylenediaminetetraacetic acid ( EDTA ) indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ].

Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.

Traditional culture methods used for hESCs are mouse embryonic fibroblasts (MEFs) as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. [ 29 ] demonstrated that hESCs cultured in the presence of animal products express the non-human sialic acid, N -glycolylneuraminic acid (NeuGc). Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor (LIF) [ 30 ].

First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year.

Initial culturing media can be serum (e.g. foetal calf serum FCS), artificial replacement such as synthetic serum substitute (SSS), knockout serum replacement (KOSR), or StemPro [ 32 ]. The simplest culture medium contains only eight essential elements: DMEM/F12 medium, selenium, NaHCO 3, l -ascorbic acid, transferrin, insulin, TGFβ1, and FGF2 [ 33 ]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

Turning point in stem cell therapy

The turning point in stem cell therapy appeared in 2006, when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This process avoided endangering the foetus’ life in the process. Retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4, and c-Myc) [ 34 ] that are mainly expressed in embryonic stem cells could induce the fibroblasts to become pluripotent (Fig.  5 ) [ 35 ]. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient. Recently, studies have focused on reducing carcinogenesis and improving the conduction system.

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body

The turning point was influenced by former discoveries that happened in 1962 and 1987.

The former discovery was about scientist John Gurdon successfully cloning frogs by transferring a nucleus from a frog’s somatic cells into an oocyte. This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R.L. that focused on fibroblast DNA subtraction. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 (Myod1), caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 (Kruppel-like factor 4). This process is enhanced by a downregulation of genes promoting genome stability, such as p53. Additionally, cell reprogramming involves histone alteration. All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. [ 40 ] checked fully pluripotent mouse iPSCs using whole genome DNA sequencing and structural variation (SV) detection algorithms. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations.

During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells. There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Source of iPSCs

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. iPSCs bypass the need for embryos in stem cell therapy. Because they are made from the patient’s own cells, they are autologous and no longer generate any risk of immune rejection.

At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method. Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. An alternative strategy to stem cell transplantation can be stimulating a patient’s endogenous stem cells to divide or differentiate, occurring naturally when skin wounds are healing. In 2008, pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ].

The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].

• Teratoma formation assay

The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. Because of the high pluripotency of teratomas, this formation assay is considered an assessment of iPSC’s abilities [ 45 ].

Teratoma formation rate, for instance, was observed to be elevated in human iPSCs compared to that in hESCs [ 46 ]. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ].

There are three groups of markers used in this assay to differentiate the cells of germ layers. For endodermal tissue, there is insulin/C-peptide and alpha-1 antitrypsin [ 49 ]. For the mesoderm, derivatives can be used, e.g. cartilage matrix protein for the bone and alcian blue for the cartilage. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes.

Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions. Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ].

Directed differentiation

To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Differentiation of ESCs is crucial because undifferentiated ESCs can cause teratoma formation in vivo. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues.

Regarding the self-renewal of embryonic stem cells, Hwang et al. [ 52 ] noted that the ideal culture method for hESC-based cell and tissue therapy would be a defined culture free of either the feeder layer or animal components. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks.

Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation. During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal intensities and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs) [ 53 ]; the Wnt family [ 54 ] or superfamily of transforming growth factors—β(TGFβ); and bone morphogenic proteins (BMP) [ 55 ]. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown. For instance, molecular antagonists of endogenous BMP and Wnt signalling can be used for ESC formation of ectoderm [ 56 ]. However, transient Wnt and lower concentrations of the TGFβ family trigger mesodermal differentiation [ 57 ]. Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ].

There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

Directed differentiation of either iPSCs or ESCs into, e.g. hepatocytes, could influence and develop the study of the molecular mechanisms in human liver development. In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ].

Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors. Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway. They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].

The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ].

The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.

Stem cell utilization and their manufacturing standards and culture systems

The European Medicines Agency and the Food and Drug Administration have set Good Manufacturing Practice (GMP) guidelines for safe and appropriate stem cell transplantation. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ].

NutriStem with LN-511, TeSR2 with human recombinant laminin (LN-511), and RegES with human foreskin fibroblasts (HFFs) are commonly used xeno-free culture systems [ 33 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ].

Stem cell use in medicine

Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

The difference between a stem cell and a differentiated cell is reflected in the cells’ DNA. In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. [ 79 ] discovered that octamer-binding transcription factor 3 and 4 (Oct3/4), sex determining region Y (SRY)-box 2 and Nanog genes function as core transcription factors in maintaining pluripotency. Among them, Oct3/4 and Sox2 are essential for the generation of iPSCs.

Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.

Haematopoietic stem cell transplantation

Haematopoietic stem cells are important because they are by far the most thoroughly characterized tissue-specific stem cell; after all, they have been experimentally studied for more than 50 years. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell (HSC) transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. The procedure can be autologous (when the patient’s own cells are used), allogenic (when the stem cell comes from a donor), or syngeneic (from an identical twin). HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets. HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations. Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. iPSC use is crucial in this procedure. The use of a patient’s own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

Stem cells as a target for pharmacological testing

Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells.

Stem cells as an alternative for arthroplasty

One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career. This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues. Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ].

Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis (OA) [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ]. Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.

Osteonecrosis of the femoral hip (ONFH) is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty (THA) is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Rejuvenation by cell programming

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in 2011 [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. This was based on an epigenetic model, which explains that at the time of fertilization, all marks of parenteral ageing are erased from the zygote’s genome and its ageing clock is reset to zero [ 95 ].

In their study, Ocampo et al. [ 96 ] used Oct4, Sox2, Klf4, and C-myc genes (OSKM genes) and affected pancreas and skeletal muscle cells, which have poor regenerative capacity. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted. In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy.

For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity.

Cell-based therapies

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.  6 ). Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ 100 ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease.

Stem cell experiments on animals. These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine

In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ 101 ].

Stem cells and tissue banks

iPS cells with their theoretically unlimited propagation and differentiation abilities are attractive for the present and future sciences. They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs.

The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.

Stem cells of human exfoliated deciduous teeth (SHED) found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ 102 ] (Table  1 ). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ 103 ]

Simple and painless for both child and parent

Less than one third of the cost of cord blood storage

Not subject to the same ethical concerns as embryonic stem cells [ 104 ]

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ 105 , 106 ]

SHED can be useful for close relatives of the donor

Fertility diseases

In 2011, two researchers, Katsuhiko Hayashi et al. [ 107 ], showed in an experiment on mice that it is possible to form sperm from iPSCs. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs .

Young adults at risk of losing their spermatogonial stem cells (SSC), mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ 108 ].

Qiuwan et al. [ 109 ] provided important evidence that human amniotic epithelial cell (hAEC) transplantation could effectively improve ovarian function by inhibiting cell apoptosis and reducing inflammation in injured ovarian tissue of mice, and it could be a promising strategy for the management of premature ovarian failure or insufficiency in female cancer survivors.

For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

Therapy for incurable neurodegenerative diseases

Thanks to stem cell therapy, it is possible not only to delay the progression of incurable neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease (AD), and Huntington disease, but also, most importantly, to remove the source of the problem. In neuroscience, the discovery of neural stem cells (NSCs) has nullified the previous idea that adult CNS were not capable of neurogenesis [ 110 , 111 ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ 112 , 113 , 114 ]. Awe et al. [ 115 ] clinically derived relevant human iPSCs from skin punch biopsies to develop a neural stem cell-based approach for treating AD. Neuronal degeneration in Parkinson’s disease (PD) is focal, and dopaminergic neurons can be efficiently generated from hESCs. PD is an ideal disease for iPSC-based cell therapy [ 116 ]. However, this therapy is still in an experimental phase ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539501 /). Brain tissue from aborted foetuses was used on patients with Parkinson’s disease [ 117 ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Stem cell use in dentistry

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells.

For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ 118 , 119 ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ 120 ]. Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ 121 ].

As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ 122 ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ 123 ].

Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ 124 ]. There are several dental stem cell groups that can be isolated (Fig.  7 ).

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and human deciduous teeth stem cells (SHED) are located in the dental pulp. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla (SCAP)

Dental pulp stem cell (DPSC)

These were the first dental stem cells isolated from the human dental pulp, which were [ 125 ] located inside dental pulp (Table  2 ). They have osteogenic and chondrogenic potential. Mesenchymal stem cells (MSCs) of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue (e.g. bone marrow, adipose tissue) and foetal (e.g. umbilical cord) [ 126 ] tissue, and they are able to differentiate densely [ 127 ]. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ 125 ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ 128 ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation (laser stimulation), which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ 129 ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth (SHED) have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e.g. other mesenchymal and non-mesenchymal stem cell derivatives, such as neural cells [ 130 ]. These cells possess one major disadvantage: they form a non-complete dentin/pulp-like complex in vivo. SHED do not undergo the same ethical concerns as embryonic stem cells. Both DPSCs and SHED are able to form bone-like tissues in vivo [ 131 ] and can be used for periodontal, dentin, or pulp regeneration. DPSCs and SHED can be used in treating, for example, neural deficits [ 132 ]. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ 133 ].

Periodontal ligament stem cells (PDLSCs)

These cells are used in periodontal ligament or cementum tissue regeneration. They can differentiate into mesenchymal cell lineages to produce collagen-forming cells, adipocytes, cementum tissue, Sharpey’s fibres, and osteoblast-like cells in vitro. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ 134 ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ 135 , 136 ].

Stem cells from apical papilla (SCAP)

These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. SCAP have a higher capacity of proliferation than DPSCs, which makes them a better choice for tissue regeneration [ 137 , 138 ].

Dental follicle stem cells (DFCs)

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ 139 , 140 ]. Additionally, these cells proliferate after even more than 30 passages [ 141 ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ 141 ]. When DFC sheets are induced by Hertwig’s epithelial root sheath cells, they can produce periodontal tissue; thus, DFCs represent a very promising material for tooth regeneration [ 142 ].

Pulp regeneration in endodontics

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp.

The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ 143 ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.

Methods of placing stem cells into the root channel constitute are either soft scaffolding [ 144 ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ 145 ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy.

The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

Acquiring non-dental tissue cells by dental stem cell differentiation

In 2013, it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.g. from urine [ 146 ]. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ 127 ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ 147 ].

Use of graphene in stem cell therapy

Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ 148 ]. Both graphene and graphene oxide (GO) represent high in-plane stiffness [ 149 ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ 148 ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ 150 ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. It was also discovered that π-π binding was responsible for increased adhesion and played a crucial role in inducing hMSC differentiation [ 150 ].

Therapeutic potential of extracellular vesicle-based therapies

Extracellular vesicles (EVs) can be released by virtually every cell of an organism, including stem cells [ 151 ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. [ 152 ] prove, stem cells, together with their paracrine factors—exosomes—can become potential therapeutics in the treatment of, e.g. skin ageing. Exosomes are small membrane vesicles secreted by most cells (30–120 nm in diameter) [ 153 ]. When endosomes fuse with the plasma membrane, they become exosomes that have messenger RNAs (mRNAs) and microRNAs (miRNAs), some classes of non-coding RNAs (IncRNAs) and several proteins that originate from the host cell [ 154 ]. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ 155 ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e.g. skin damage and renal or lung injuries [ 156 ].

In skin ageing, the most important factor is exposure to UV light, called “photoageing” [ 157 ], which causes extrinsic skin damage, characterized by dryness, roughness, irregular pigmentation, lesions, and skin cancers. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity. Fibroblast efficiency and abundance decrease with ageing [ 158 ]. Stem cells can promote the proliferation of dermal fibroblasts by secreting cytokines such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), and basic fibroblast growth factor. Huh et al. [ 159 ] mentioned that a medium of human amniotic fluid-derived stem cells (hAFSC) positively affected skin regeneration after longwave UV-induced (UVA, 315–400 nm) photoageing by increasing the proliferation and migration of dermal fibroblasts. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ 160 , 161 ].

Oh [ 162 ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium (iPSC-CM) without any animal-derived components induced dermal fibroblast proliferation and migration.

Natural cutaneous wound healing is divided into three steps: haemostasis/inflammation, proliferation, and remodelling. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ 163 ]. These actions result in the secretion of cytokines such as TGF-β, interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and basic fibroblast growth factor (bFGF). Bae et al. [ 164 ] mentioned that TGF-β induced the migration of keratinocytes. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. [ 165 ] enhanced wound healing, even after carbon dioxide laser resurfacing in an in vivo study.

Peng et al. [ 166 ] investigated the effects of EVs derived from hESCs on in vitro cultured retinal glial, progenitor Müller cells, which are known to differentiate into retinal neurons. EVs appear heterogeneous in size and can be internalized by cultured Müller cells, and their proteins are involved in the induction and maintenance of stem cell pluripotency. These stem cell-derived vesicles were responsible for the neuronal trans-differentiation of cultured Müller cells exposed to them. However, the research article points out that the procedure was accomplished only on in vitro acquired retina.

Challenges concerning stem cell therapy

Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern.

The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in 1998, scientists discovered the possibility of removing ESCs from human embryos. Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed (Fig.  8 ). Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types

For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. The second problem is to achieve successful immunological tolerance between stem cells and the patient’s body. For now, one of the best ideas is to use the patient’s own cells and devolve them into their pluripotent stage of development.

New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ 167 ].

One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In 2008, a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time. The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. At first, the rate of somatic cell reprogramming in Yamanaka’s study was up to 0.1%. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ 168 ].

Stem cell obstacles in the future

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently.

Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome.

The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

The identification and proper isolation of stem cells from a patient’s tissues is another challenge. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

One of the ideas that can make stem cells a “failsafe” is about implementing a self-destruct option if they become dangerous. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects.

Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions. Their impact on future medicine appears to be significant.

After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Induced pluripotency enables the use of a patient’s own cells. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

Abbreviations

Basic fibroblast growth factor

Bone morphogenic proteins

Dental follicle stem cells

Dental pulp stem cells

Embryonic bodies

Embryonic stem cells

Fibroblast growth factors

Good Manufacturing Practice

Graphene oxide

Human amniotic fluid-derived stem cells

Human embryonic stem cells

Human foreskin fibroblasts

Inner cell mass

Non-coding RNA

Induced pluripotent stem cells

In vitro fertilization

Knockout serum replacement

Leukaemia inhibitory factor

Monocyte chemotactic protein-1

Fibroblasts

Messenger RNA

Mesenchymal stem cells of dental pulp

Myogenic differentiation

Osteoarthritis

Octamer-binding transcription factor 3 and 4

Platelet-derived growth factor

Platelet-derived growth factor-AA

Periodontal ligament stem cells

Rho-associated protein kinase

Stem cells from apical papilla

Stem cells of human exfoliated deciduous teeth

Synthetic Serum Substitute

Trophectoderm

Vascular endothelial growth factor

Transforming growth factors

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Wojciech Zakrzewski, Maria Szymonowicz & Zbigniew Rybak

Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland

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WZ is the principal author and was responsible for the first draft of the manuscript. WZ and ZR were responsible for the concept of the review. MS, MD, and ZR were responsible for revising the article and for data acquisition. All authors read and approved the final manuscript.

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Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. et al. Stem cells: past, present, and future. Stem Cell Res Ther 10 , 68 (2019). https://doi.org/10.1186/s13287-019-1165-5

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Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice

Salomon poliwoda.

1 Department of Anesthesiology, Mount Sinai Medical Center

2 LSU Health Science Center Shreveport School of Medicine, Shreveport, LA

Amanda Schaaf

3 University of Arizona College of Medicine-Phoenix, Phoenix, AZ

Abigail Cantwell

Latha ganti.

4 Department of Emergency Medicine, University of Central Florida

Alan D. Kaye

5 Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport

Luke I. Mosel

Caroline b. carroll, omar viswanath.

6 Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Innovative Pain and Wellness, Creighton University School of Medicine

Stem cells are types of cells that have unique ability to self-renew and to differentiate into more than one cell lineage. They are considered building blocks of tissues and organs. Over recent decades, they have been studied and utilized for repair and regenerative medicine. One way to classify these cells is based on their differentiation capacity. Totipotent stem cells can give rise to any cell of an embryo but also to extra-embryonic tissue as well. Pluripotent stem cells are limited to any of the three embryonic germ layers; however, they cannot differentiate into extra-embryonic tissue. Multipotent stem cells can only differentiate into one germ line tissue. Oligopotent and unipotent stem cells are seen in adult organ tissues that have committed to a cell lineage. Another way to differentiate these cells is based on their origins. Stem cells can be extracted from different sources, including bone marrow, amniotic cells, adipose tissue, umbilical cord, and placental tissue. Stem cells began their role in modern regenerative medicine in the 1950’s with the first bone marrow transplantation occurring in 1956. Stem cell therapies are at present indicated for a range of clinical conditions beyond traditional origins to treat genetic blood diseases and have seen substantial success. In this regard, emerging use for stem cells is their potential to treat pain states and neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Stem cells offer hope in neurodegeneration to replace neurons damaged during certain disease states. This review compares stem cells arising from these different sources of origin and include clinical roles for stem cells in modern medical practice.

I. Introduction

Stem cells are a unique population of cells present in all stages of life that possess the ability to self-renew and differentiate into multiple cell lineages. These cells are key mediators in the development of neonates and in restorative processes after injury or disease as they are the source from which specific cell types within differentiated tissues and organs are derived. 1 Within the neonate stage of life stem cells serve to differentiate and proliferate into the multitude of cell types and lineages required for continuing development, while in adults their primary role is regenerative and restorative in nature. 2 Stem cells have unique properties that set them apart from terminally differentiated cells allowing for their specific physiological roles. The ability of stem cells to differentiate into multiple cell types is termed potency, and stem cells can be classified by their potential for differentiation as well as by their origin. Totipotent or omnipotent stem cells can form embryonic tissues and can differentiate into all cell lineages required for an adult. Pluripotent stem cells can differentiate into all three germ layers while multipotent stem cells may only differentiate into one kind of germ line tissue. Oligopotent and unipotent stem cells are the type seen in adult organ tissues that have committed to a cell lineage and can only diversify into cell types within that lineage. 1 Embryonic stem cells are derived from the inner cell mass of a blastocysts and are totipotent. The range of their use is typically restricted due to legal and ethical factors and for this reason mesenchymal stem cells are typically preferred. Mesenchymal stem cells can be isolated from a variety of both neonate and adult tissues but still maintain the ability to differentiate into multiple cell types allowing for their clinical and research utilization without the ethical issues associated with embryonic stem cells. 3

Another key feature of stem cells is their ability to self-renew and proliferate providing a continuous supply of progeny to replace aging or damaged cells. During the developmental phase this proliferation allows for the growth necessary to mature into an adult. After the developmental phase has concluded, this continued proliferation allows for healing and restoration on a cellular level after tissue or organ injury has taken place. 2 These physiological and developmental characteristics make stem cells an integral part in the field of regenerative medicine due to their ability to generate entire tissues and organs from just a handful of progenitor cells.

Stem cells began their role in modern regenerative medicine in the 1950’s with the first bone marrow transplantation occurring in 1956. This breakthrough shed light on the potential treatments possible in the future with further development and refinement of clinical techniques and paved the way for the stem cell therapies that are now available. 4,5 Stem cell therapies are now indicated for a range of clinical conditions beyond traditional origins to treat genetic blood diseases and have seen substantial success where other treatments have fallen short. One emerging use for stem cells is their potential to treat paint states and neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Stem cells offer the hope in the setting of neurodegeneration to replace the neurons damaged during the pathogenesis of certain diseases, a goal not achievable utilizing current technologies and methods. 6

Organ bioengineering is yet another a rapidly developing and exciting new application for stem cells with both clinical and research implications. 7 Immunosuppression free organ transplants are now a possibility with the advancement organ manufacturing utilizing the patient’s own cells. 8 This along with the potential for eliminating organ donor waiting lists is an enticing prospect, but many technological developments are necessary before this technology can be implemented in clinical settings on a wide scale. Research has already benefitted greatly from this field because organ like tissues can be grown in lab settings to model disease progression. This offers the potential to develop new treatments while determining their efficacy on a cellular level without risk to patients. 9,10

Currently one of the most prolific clinical uses of stem cells in the field of regenerative medicine is to treat inherited blood diseases. Within these diseases a genetic defect or defects prevents the proper function of cells derived from the hematopoietic stem cell lineage. Treatment includes implantation of genetically normal cells from a healthy donor to serve as a lifelong self-renewing source of normally functioning blood cells. However these treatments are limited by the availability of suitable donors. 11

Stem cells can be derived from multiple sources including adult tissues or neonatal tissues such as the umbilical cord or placenta. Embryonic stem cells have been utilized in the past for research, but ethical concerns have led to them being replaced largely by stem cells derived from other origins. 12 Common tissues from which adult oligopotent and unipotent stem cells are isolated include bone marrow, adipose tissue, and trabecular bone. 13 Bone marrow has traditionally been the most common site from which to extract non neonatal derived stem cells but involves an invasive and painful procedure. Peripheral blood progenitor cells have been utilized to avoid harvesting cells from bone marrow. However, this technique has issues and risks of its own and was initially a less potent source of stem cells. It is also now known that stem cells differ in their proliferative and differentiation potential based on their origin. Cells sourced from umbilical Wharton’s jelly and adipose tissue were found to proliferate significantly more quickly than cells sourced from bone marrow and placental sources. 14,15

A rapidly advancing source of stem cells known as induced pluripotent stem cells (iPSC’s) are now being utilized clinically as well. These iPSC’s are derived from somatic cells that have been reprogrammed back to a pluripotent state utilizing reprogramming factors and require less invasive techniques to harvest in comparison to traditional sources. 16,17 Once returned to a pluripotent state, the cells then undergo a process called directed differentiation in which they are converted into desired cell types. Directed differentiation is achieved by mimicking microenvironments and extracellular signals in vitro in a manner that produces predictable cell types. 18 In the future, this technique could provide a novel form of personalized gene therapy in which oligopotent or unipotent cells are procured from tissue, reprogrammed back to a less differentiated state, and then reintroduced into a different location within the patient. Work is also being done to combine this technique with modern gene editing methods to provide an entirely new subset of therapies. 19 This method of transplantation would greatly reduce the chance for rejection and does not require a suitable donor, as the cells are sourced from the patient being treated. 20,21

II. Bone marrow as a source for stem cells

Stem cells are required by self-renewing tissues to replace damaged and aging cells because of normal biological processes. Both myeloid and lymphoid lineage cells derived from hematopoietic stem cells are relatively short-lived cell types and require a continuous source of newly differentiated replacement cells. 22 Hematopoietic stem cells (HSC’s) are those that reside within the bone marrow and provide a source for the multiple types of blood cells required for normal physiological and immunological functions. These cells inhabit a physiological niche which allows them to undergo the process of asymmetric division. When stem cells divide asymmetrically the progeny of the division includes one identical daughter cell but also results in the production of a differentiated daughter cell. Differentiation of these daughter cell into specialized cell types is guided by certain microenvironments, extrinsic cues, and growth factors that the cell comes in contact with. 23,24 This mechanism allows for bone marrow stem cell numbers to stay relatively constant despite sustained proliferation and differentiation of progeny taking place. 22,25,26

HSC’s are the most studied class of adult tissue derived stem cells and their clinical potential was recognized early in the history of regenerative medicine. At the beginning of the 1960’s, HSC’s were isolated from bone marrow and therapeutic models in mice induced with leukemia were developed in order to show the efficacy of bone marrow derived stem cell treatments. Success in these experiments led to further refinement of techniques and by the 1970’s and 80’s clinical stem cell transplants were a regular occurrence and began to make the impact on blood diseases that we continue to see today. 27,28

Bone marrow has historically been the predominant harvesting site for stem cell collection due to its accessibility, early identification as a source, and lengthy research history. Isolating stem cell from bone marrow involves an invasive and painful surgical procedure and does come with a risk hospitalization or other complications. Patients also report increased post procedural pain and pre-procedural anxiety when compared with other harvesting techniques. 29,30 Bone marrow however has proved to be a denser source of cells than other harvesting methods yielding 18 times more cells than peripheral blood progenitor cell harvesting techniques initially. As technology and methods improved however, it was found that treating patients with a cytokine treatment prior to peripheral blood progenitor cell harvesting mobilized many of the desired cells into the blood stream and drastically increased the efficacy of this technique, making it clinically viable. 31–33 In a double blinded randomized study 40 patients underwent bone marrow and peripheral blood progenitor cell collections and the yield of useable harvested cells were compared. It was found that blood progenitor cell collection yielded significantly more useable stem cells and patients were able to undergo the collection procedure more frequently when compared to the bone marrow harvesting method. 32 This, coupled with the invasiveness and risks associated with harvesting stem cells from bone marrow have increased peripheral blood progenitor cell collections popularity.

Overall, bone marrow as a reservoir of stem cells continues to be a clinical and research necessity related to its well understood and documented history as a source of viable stem cells and track record of efficacy. According to the European Group for Blood and Marrow Transplantation, only one fatal event was recorded stemming from the first 27,770 hematopoietic stem cell transplants sourced from bone marrow during the period of 1993-2005. 34 This undeniable track record of safety coupled with clinicians’ experience performing bone marrow transplant procedures guarantees the continued use of bone marrow as a source of HSC’s for the near future.

III. Amniotic cells as a source for stem cells

Historically, the two most common types of pluripotent stem cells include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). 35 However, despite the many research efforts to improve ESC and iPSC technologies, there are still enormous clinical challenges. 35 Two significant issues posed by ESC and iPSC technologies include low survival rate of transplanted cells and tumorigenicity. 35 Recently, researchers have isolated pluripotent stem cells from gestational tissues such as amniotic fluid and the placental membrane. 35 Human amnion-derived stem cells (hADSCs), including amniotic epithelial cells and amniotic mesenchymal cells, are a relatively new stem cell source that have been found to have several advantageous characteristics. 35,36

For background, human amniotic stem cells begin emerging during the second week of gestation when a small cavity forms within the blastocyst and primordial cells lining this cavity are differentiated into amnioblasts. 36 Human amniotic epithelial stem cells (hAESCs) are formed when epiblasts differentiate into amnioblasts, whereas human amniotic mesenchymal stem cells (hAMSCs) are formed when hypoblasts differentiate into amnioblasts. 35,36 This differentiation occurs prior to gastrulation, so amnioblasts do not belong to one of the 3 germ layers, making them theoretically pluripotent. 35–37

Previously, pluripotency and immunomodulation are qualities that have been thought to be mutually exclusive, as pluripotency has traditionally been regarded as a characteristic limited to embryonic stem cells whereas immunomodulation has been a recognized property of mesenchymal stem cells. 36 However, many recent studies have found that these two qualities coexist in hADSCs. 35,36

In recent years, hADSCs, including human amniotic epithelial stem cells (hAESCs) and human amniotic mesenchymal stem cells (hAMSCs) have been attractive cell sources for clinical trials and medical research, and have been shown to have advantages over other stem cells types. 35,37 These advantages include low immunogenicity and high histocompatibility, no tumorigenicity, immunomodulatory effects, and significant paracrine effects. 35 Also, several studies have evaluated the proangiogenic ability of hADSCs. 35 Interestingly, they found that hAMSCs were shown to augment blood perfusion and capillary architecture when transplanted into ischemic limbs of mice, suggesting that hAMSCs stimulate neovascularization. 35,38 Additionally, another advantage is that hADSCs are easier to obtain compared to other stem cell sources, such as bone marrow stem cells (BMSCs). 35

Regarding the low immunogenicity, hADSCs have been shown to have a low expression of major histocompatibility class I antigen ( HLA-ABC ), and no expression of major histocompatibility class II antigen ( HLA-DR ), β2 microglobulin, and HLA-ABC costimulatory molecules, including CD40, CD80 and CD8635. Notably, there have been reports of transplantation of hAMSCs into patients with lysosomal diseases who had no obvious rejection. 35 Moreover, a recent study demonstrated no hemolysis, allergic reactions, or tumor formations in mice who received intravenous hAESCs. 35,39

Additionally, studies have demonstrated that both hAESCs and hAMSCs have great potential to play an important role in regenerative medicine. They both have demonstrated that they can differentiate into several specialized cells, including adipocytes, bone cells, nerve cells, cardiomyocytes, skeletal muscle cells, hepatocytes, hematopoietic cells, endothelial cells, kidney cells, and retinal cells. 35

Multiple preclinical studies have revealed the potential for hADSCs to be used in the treatment of several diseases including premature ovarian failure, diabetes mellitus, inflammatory bowel disease, brain/spine diseases, and more. 35,40,41 For example, one preclinical study investigated the effect of hAMSC-therapy on ovarian function in natural aging ovaries within mice. 40 They found that after the hAMSCs were transplanted into the mice, the hAMSCs significantly improved follicle proliferation and therefore ovarian function. 40 Another study investigated the effect of hAESC-therapy on outcomes after stroke in mice. 41 They found that, administration of hAESCs after acute (within 1.5 hours) stroke in mice reduced brain infarct development, inflammation, and functional deficits. 41 Additionally, they found that after late administration (1-3 days poststroke) of hAESCs, functional recovery in the mice was still improved. 41 Overall, they concluded that administration of hAESCs following a stroke in mice showed a significant neuroprotective effect and facilitated repair and recovery of the brain. 41

Although a number of preclinical studies, like the ones previously described, have shown considerable promise regarding the use of ADSC-therapy, more studies are needed. Future studies can continue to work toward determining if hADSCs are capable of being used for cell replacement and better elucidate the mechanisms by which hADSCs work.

IV. Adipose tissue as a source for stem cells

Although the use of bone marrow stem cells (BMSCs) is now standard, dilemmas regarding harvesting techniques and the potential for low cell yields has driven researchers to search for other mesenchymal stem cell (MSCs) sources. 42 One source that has been investigated is human adipose tissue. 42

After enzymatic digestion of adipose tissue, a heterogenous group of adipocyte precursors are generated within a group of cells called the stromal vascular fraction (SVF). 42 Adipose-derived stem cells (ADSCs) are found in the SVF. 42,43 Studies have demonstrated that ADSCs possess properties typically associated with MSCs, and that they have been found to express several CD markers that MSCs characteristically express. 43 ADSCs are multipotent and have been shown to differentiate into other cells of mesodermal origin, including osteoblasts, chondroblasts, myocytes, tendocytes, and more, upon in vitro induction. 42–45 Additionally, ADSCs have demonstrated in vitro capacity for multi-lineage differentiation into specialized cells, like insulin-secreting cells. 43,46

A significant advantage of ADSCs over BMSCs is how easy they are to harvest. 43,45 White adipose tissue (WAT) contains an abundance of ADSCs. 43 The main stores of WAT in humans are subcutaneous stores in the buttocks, thighs, abdomen and visceral depots. 43 Due to this, ADSCs can be harvested relatively easily by liposuction procedures from these areas of the body. 43,45 Moreover, ADSCs make up as much as 1-2% of the SVF within WAT, sometimes even nearing 30% in some tissues. 43,45 This is a significant difference from the .0001-.0002% stem cells present in bone marrow. 43 Given this difference in stem cell concentration between the sources, there will be more ADSCs per sample of WAT compared to stem cells per bone marrow sample, further demonstrating an easier acquisition of stem cells when using adipose tissue.

Another advantage of ADSCs is their immune privilege status due to a lack of major histocompatibility complex II (MHC II) and costimulatory molecules. 42,43,45,47 Some studies have even demonstrated a higher immunosuppression capacity in ADSCs compared to BMSCs as ADSCs expressed lower levels of human antigen class I (HLA I) antigen. 47 They also have a unique secretome and can produce immunomodulatory, anti-apoptotic, hematopoietic, and angiogenic factors that can help with repair of tissues – characteristics that may support successful transplantations without the need for immunosuppression. 42–45 Moreover, ADSCs have the ability to be reprogrammed to induced pluripotent stem (iPS) cells. 43

The number of ADSC clinical trials has risen over the past decade, and some have shown significant promise. They have demonstrated abilities to differentiate into multiple cell lines in a reproducible manner and be safe for both autogenetic and allogeneic transplantations. 45 Several recent studies have demonstrated that ADSC-therapy may potentially be useful in the treatment of several conditions, including diabetes mellitus, Crohn’s disease, multiple sclerosis, fistulas, arthritis, ischemic pathologies, cardiac injury, spinal injury, bone injuries and more. 44–48

One clinical trial conducted in 2013 investigated the therapeutic effect of co-infusion of autologous adipose-derived differentiated insulin-secreting stem cells and hematopoietic stem cells (HSCs) on patients with insulin-dependent diabetes mellitus. 46 Ten patients were followed over an average of about thirty-two months, and they found that all the patients had improvement in C-peptide, HbA1c, blood sugar status, and exogenous insulin requirement. 46 Notably, there were no unpleasant side effects of the treatment and all ten patients had rehabilitated to a normal, unrestricted diet and lifestyle. 46

In another 4-patient clinical trial in which ADSCs were used to heal fistulas in patients with Crohn’s disease, full healing occurred in 6 out of the 8 fistulas with partial healing in the remaining two. 44 No complications were observed in the patients 12 months following the trial. 44 Although these results are promising, the mechanism by which the healing took place remains unclear. When considering the properties of ADSCs, there are a number of factors that could have played a role in the healing, such as the result of paracrine expression of angiogenic and/or anti-apoptotic factors, stem cell differentiation, and/or local immunosuppression. 44

Other exciting studies have demonstrated a use of ADSCs in the treatment of osteoarthritis (OA). One meta-analysis compared the use of ADSCs and BMSCs in the treatment of osteoarthritis. 47 This meta-analysis included 14 studies comprising 461 original patient records. 47 Overall, the comparison between treatment of OA didn’t show a significant difference in the disease severity score change rate between patients treated with ADSCs and those treated with BMSCs. 47 However, there was significantly more variability in the outcomes of those treated with BMSCs with the highest change rate being 79.65% in one study and the lowest being 22.57% in another study. 47 Given this, ADSCs may represent a more stable cell source for the treatment of OA. 47 Although this study is specific to OA treatment, it is worth acknowledging the possibility that ADSCs may also represent a more stable cell source for treatment of other diseases as well.

Though recent ADSC research, as described above, has been promising, unfortunately reproducible in vivo studies are still lacking in both quality and quantity. 42 Therefore, further studies are necessary prior to progression to routine patient administration. 42

V. Umbilical Cord as a source for stem cells

Umbilical Cord stem cells can be drawn from a variety of locations including umbilical cord blood, umbilical cord perivascular cells, umbilical vein endothelial cells, umbilical lining, chorion, and amnion. Umbilical cord blood can be drawn with minimal risk to the donor, and it has been used since 1988 as a source for hematopoietic stem cells. 49 When compared to stem cells obtained from bone marrow, umbilical cord derived stem cells are much more readily available. With a birth rate of more than a 100 million people per year globally, there is a lot of opportunity to use umbilical cord blood as a source for stem cells.

The process of extracting the blood is very simple and involves a venipuncture followed by drainage into a sterile anti-coagulant-filled blood bag. It is then cryopreserved and stored in liquid nitrogen. There are quite a few benefits to utilizing umbilical cord stem cells rather than stem cells drawn from adults. One of the biggest benefits is that the cells are more immature which means that there is a lower chance of rejection after implantation in a host and would lead to decreased rates of graft-versus-host disease. They also can differentiate into a very wide variety of tissues. For example, when compared with bone marrow stem cells or mobilized peripheral blood, umbilical cord blood stem cells have a greater repopulating ability. 50 Cord blood derived CD34+ cells have very potent hematopoietic abilities, and this is attributed to the immaturity of the stem cells relative to adult derived cells. Studies have been done that analyze long term survival of children with hematologic disorders who were transplanted with umbilical cord blood from a sibling donor. These studied revealed the same or better survival in the children that received the umbilical cord blood relative to those that got transplantation from bone marrow cells. Furthermore, rates of relapse were the same for both umbilical cord blood and bone marrow transplant. 51

One of the unique features of stem cells taken from umbilical cord blood is the potential to differentiate into a wide variety of cell types. There are three different kinds of stem cells that can be found in the umbilical cord blood which include hematopoietic, mesenchymal, and embryonic-like stem cells. Not only can these cell types all renew themselves, but they can differentiate into many different mature cell types through a complex number of signaling pathways. This means that these cells could give rise to not only hematopoietic cells but bone, neural and endothelial cells. There are studies taking place currently to see if umbilical cord blood derived stem cells can be utilized for cardiomyogenic purposes. Several studies have showed the ability to transform umbilical cord blood mesenchymal stem cells into cells of cardiomyogenic lineage utilizing activations of Wnt signaling pathways. 52 Studies are also being conducted on the potential of neurological applications. If successful, this could help diseases such as cerebral palsy, stroke, spinal cord injury and neurodegenerative diseases. Given these cell’s ability to differentiate into tissues from the mesoderm, endoderm and ectoderm, they could be utilized for neurological issues in place of embryonic stem cells that are currently extremely controversial. 53 There are currently studies involving in vitro work, pre-clinical animal studies, and patient clinical trials, all for the application of stem cells in neurological applications. There is big potential for the use of umbilical blood stem cells in the future of regenerative medicine.

VI. Placental Tissue as a Source for Stem Cells

Placental tissue contains both stem cells and epithelial cells that can differentiate into a wide variety of tissue types which include adipogenic, myogenic, hepatogenic, osteogenic, cardiac, endothelial, pancreatic, pulmonary, and neurological. Placental cells can differentiate in to all these different kinds of tissues due to lineages originating from different parts of the placenta such as the hematopoietic cells that come from the chorion, allantois, and yolk sac while the mesenchymal lineages come from the chorion and the amnion. 54 It can be helpful to think of human fetal placental cells as being divided into four different groups: amniotic epithelial cells, amniotic mesenchymal stromal cells, chorionic mesenchymal stromal cells and chorionic trophoblast cells. 54

Human amniotic epithelial cells (hAECs) can be obtained from the amnion membrane where they are then enzymatically digested to be separated from the chorion. When cultured under certain settings hAECs have been found to be able to produce neuronal cells that synthesize acetylcholine, norepinephrine as well as dopamine. 55,56 This ability would mean they have potential for regenerative purposes in diseases such as Parkinson’s Disease, multiple sclerosis, and spinal cord injury. There is also research being done to utilize hAECs for ophthalmological purposes, lung fibrosis, liver disease, metabolic diseases, and familial hypercholesterolemia. Once cultured, hAECs have been shown to produce both albumin and alpha-fetoprotein as well as showing ability to store glycogen. Furthermore, they have been found to metabolize ammonia and testosterone. In more recent studies conducted in mouse models, these cells have been found to have therapeutic efficacy after transplantation for cirrhosis. 57

Mesenchymal stem cells are in many different tissues such as the bone marrow, umbilical cord blood, adipose tissue, Wharton’s jelly, amniotic fluid, lungs, muscle and the placenta. Placental mesenchymal stromal cells specifically originate from the extraembryonic mesoderm. Human amniotic mesenchymal stromal cells (hAMSCs) and chorionic mesenchymal stromal cells (hCMSCs) have both been found to have very low levels of HLA-A,B,C. This means that they have immune privileged profiles for potential transplantation. 58,59 Placental derived mesenchymal stem cells have been shown to have expression of CD29, CD44, CD105 and CD166 which is the same as adipose derived mesenchymal stem cells. These markers have been shown to have osteogenic differentiating abilities. 57 An interesting element of placental mesenchymal stem cells is that their properties differ depending on the gestational age of the placenta. When cells are harvested at lower gestational ages, they show faster generation doubling times, better proliferative abilities, wider differentiation potential and more phenotypic stability than cells harvested from placental tissue that is considered to be at term. 60 Furthermore, they have great potential to be used clinically. Placental mesenchymal stromal cells have been studied for use in treating acute graft-versus-host disease that was refractory to steroid treatment. Studies have shown that the 1-year survival rates in patients treated with placenta derived stromal cells were 73% while retrospective control only showed 6% survival. 61 Placenta derived MSCs have also been found to aid in wound healing and could potentially be used to aid with certain inherited skin conditions such as epidermolysis bullosa. 62

Stem cells are diverse in their differentiation capacity as well as their source of origin. As we can see from this review, there are similarities and differences when these cells are extracted from different sources. Research has shown initial promise in neurodegenerative diseases such as Alzheimer’s and Parkinson’s Disease. It has also shown to be beneficial in the areas of musculoskeletal regenerative medicine and other pain states. Organ bioengineering for transplantation is another potential benefit that stem cells may offer. For these reasons, extensive research is still needed in this area of medicine to pave the way for new developing therapy modalities.

Conflict of Interest of each author

Dedications.

This review is dedicated to Dr. Justine C. Goldberg MD

Funding Statement

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A developmental route to hematopoietic stem cells

• Adam C. Wilkinson   ORCID: orcid.org/0000-0001-7406-0151 1 &
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A differentiation method informed by developmental biology converts human pluripotent stem cells to engraftable hematopoietic stem and progenitor cells without the use of transgenes.

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A comprehensive review of challenges and opportunities for stem cell research in India

Srivastava, Kavita; Srivastava, Lily 1 ; Jain, Tanvi

Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University , Barabanki, UP, India

1 Department of Law, Sri J.N.M.P.G College, Associated College of Lucknow University, Lucknow, UP, India

Address for correspondence: Dr. Tanvi Jain, Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Barabanki, Uttar Pradesh, India. E-mail: [email protected]

Stem cell research is a major focus for scientific and medical communities worldwide due to the potential for stem cells to restore function lost due to disease, trauma, congenital abnormalities, and aging. Stem cells can repair, replace, or regenerate damaged cells, tissues, or organs, making them an important area of research in regenerative medicine. India is emerging as a prominent hub for the development of stem cell therapy (SCT), and it is important to assess the current state of stem cell research in India and the potential for advancement to promote stem cell-based therapy. However, several barriers exist in India that are hindering the rapid expansion of SCT. This article examines the existing regulations that govern SCT in India, comparing them with regulations in developed nations, particularly for patients with unmet clinical needs. It also highlights the importance of public education in dispelling myths, addressing concerns, and promoting the benefits of stem cell research. The article concludes with recommendations for enhancing safety measures in SCT applications to ensure ethical practices and patient well-being.

INTRODUCTION

Stem cells hold immense promise for regenerative medicine (RM), offering potential treatments for a wide range of untreatable conditions by repairing and replacing damaged tissues. [ 1 ] Contrarily, ethical debates often focus on embryonic stem cells (ESCs) due to concerns about destroying human embryos. In contrast, adult stem cells and induced pluripotent stem cells present alternative approaches that bypass ethical concerns associated with ESCs. However, they also come with their own set of challenges such as immune rejection, teratoma formation, grafted cell escape, and microbial contamination in producing clinical-grade stem cells. [ 2 ] In addition to the research challenges, several other hindrances need to be addressed to stop the unproven stem cell therapy (SCT) practices in India.

Medical facilities promoting SCT without adequate clinical evidence call for a thorough investigation to ensure patient safety. For instance, a hospital in New Delhi and another in Chennai received criticism for promoting SCT without supporting evidence. [ 3 ] In December 2022, a top hospital in Mumbai lost its license because it was offering and advertising SCT to treat autism in children, which is not an accepted standard treatment for autism as per the Indian Council of Medical Research (ICMR)’s official website. [ 4 ] These cases highlight the need to address the gap in the regulation of SCT, aimed at protecting patients.

The purpose of this article is to examine, India’s current state of stem cell research, identifies regulatory challenges, and highlight opportunities for advancement.

The article compares the regulatory frameworks for SCT in the United States (US), the European Union (EU), and Japan, with a specific focus on innovative conditional approval approaches for experimental SCT targeting unmet clinical needs in both India and developed nations. Finally, the article concludes with actionable recommendations to rest unproven SCT proliferation and highlights India’s potential as a health-care system.

METHODOLOGY

PubMed and Google were searched for using specific keywords, “stem cell,” “unproven,” “unregulated,” “regenerative medicine,” “tourism,” “global,” “challenges,” “adverse events,” “expedite,” “conditional,” “compassionate,” and “clinic.” The authors searched for mass media reports to gather relevant evidence. The Indian legal and policy developments about stem cell research were searched to map the existing laws, guidelines, and regulations introduced by the Government of India. In addition, official documents and scientific literature from regulatory agencies in the US, EU, and Japan were also reviewed.

Stem cells have demonstrated promising potential in treating a wide range of diseases, including stroke, Parkinson’s disease, spinal cord injury, cerebellar ataxias, multiple sclerosis, motor neuron disease, cancer, and diabetes. [ 1 ] To examine the current status of stem cell trials, a pie chart was created by searching data from the US clinical trial registry ( https://www.clinicaltrials.gov/ ) up to March 2023 with stem cell-related keywords. This chart, displayed in Figure 1 , provides a breakdown of SCT by disease indication. According to the chart, clinical trials primarily focused on cancer (55%), followed by cardiovascular disease (24%), neurological diseases (11%), diabetes (3%), osteoarthritis (3%), COVID-19 (2%), and liver disease (2%).

SCT holds immense potential in treating various diseases and injuries. Nevertheless, significant challenges associated with SCT exist across different domains, including biological, manufacturing, and pharmacological aspects. Biological challenges include the risk of immune rejection and the potential for stem cells to develop into cancer, emphasizing the importance of rigorous monitoring and research. Manufacturing challenges require characterizing and predicting cell products to ensure it is free of contamination. In vitro , cultivation should maintain the genotypic and phenotypic characteristics of stem cells in a healthy state for successful SCT. [ 5 ] Pharmacological challenges involve translating animal studies into humans, especially in dosing and pharmacokinetics. Proper localization and distribution of transplanted stem cells are crucial for understanding their pharmacokinetic behavior. Further research is needed to understand the graft’s interaction with the host’s immunity, as the potential for immunotoxicity is not fully understood.

GOVERNMENT INITIATIVES PROMOTING STEM CELL THERAPY IN INDIA

The government has implemented legislative measures such as the National Biotechnology Development Strategy 2020–2025 and Technology Vision 2035 to advance SCT, focusing on capacity building, infrastructure development, and strategic investments. Government agencies such as the Biotechnology Industry Research Assistance Council and the Department of Biotechnology (DBT) promote stem cell research and development, fostering innovation through RM partnerships. From 2019 to 2021, both DBT and ICMR showed significant commitment to stem cell research. DBT allocated funds for various projects, whereas ICMR funded fellowships and ad hoc projects. [ 6 ] Several Indian Research Institutes and Medical Centers, including the National Brain Research Centre in Manesar, the Institute of Stem Cell Science and RM in Bengaluru, the All India Institute of Medical Sciences in New Delhi, and Christian Medical College in Vellore, are actively promoting stem cell interventions, contributing to scientific knowledge and medical advancements.

CURRENT STATUS OF STEM CELL THERAPY IN INDIA

REGULATORY FRAMEWORK FOR STEM CELL RESEARCH AND THERAPY IN INDIA

The National Guidelines for Stem Cell Research (NGSCR) 2017 is the key document in India that regulates stem cell activities which underwent revisions in 2013 and 2017. [ 10 ] According to the NGSCR 2017, stem cells are categorized under the Drugs and Cosmetics Act 1940 as “Investigational New Drugs” or “Investigational New Entities.” NGSCR 2017 mandates that the use of stem cells in patients outside of an approved clinical trial is considered unethical and shall be considered malpractice except for hematopoietic stem cells. The NGSCR categorizes stem cells into three levels: minimal, substantial, and more than minimal, with guidelines outlining the necessary approvals for each category. Companies must obtain approval from the Central Drug Standard Control Organization (CDSCO) before conducting clinical trials and marketing, stem cell or cell-based products (SCCPs) in India.

The NGSCR 2017 distinguishes between institutional and national monitoring methods. The Institutional Committee of Stem Cell Research oversees research operations at the institutional level, and the National Apex Committee for SCRT (NAC-SCRT) oversees research activities at the national level. The Cell Biology-Based Therapeutic Drugs Evaluation Committee, established by CDSCO, assesses the safety and efficacy of SCCPs in India by evaluating Chemistry, Manufacturing, and Control data, preclinical and clinical trial data, and manufacturing or import standards.

The NGSCR 2017 stresses the importance of conditional approval for SCT, expediting the availability of life-saving treatments. [ 10 ] India’s proposed amendments to the New Drugs and Clinical Trial Rules (NDCTR) 2019 aim to allow compassionate use of drugs, granting patients access to promising therapies during clinical testing, particularly when standard treatments are ineffective or unavailable. [ 11 ] However, in India, experimental drugs necessitate conditional approval for import or prescription by government health-care professionals post-Phase III clinical trials, either domestically or internationally.

CHALLENGES FACED BY STEM CELL REGULATION IN INDIA

Stem cell regulation in India faces challenges due to the absence of specific legislation, which can be exploited by unscrupulous practitioners. [ 12 ] The Ministry of Health and Family Welfare, Government of India amended the Drugs and Cosmetics Rules, 1945 in 2018, defining SCCPs as drugs obtained from processed cells through substantial manipulation. [ 13 ] Anyway, this definition excludes minimally manipulated stem cells, creating a regulatory loophole. ICMR disagreed with a proposed amendment that would exempt minimally manipulated stem cells from classification as drugs, arguing it could contravene the principles outlined in the NGSCR 2017. [ 14 ] The imprecise definition of SCCPs is causing a regulatory vacuum in the enforcement of SCT in India.

Direct-to-consumer advertising in the field of SCT has led to exaggerated expectations regarding the availability and effectiveness of such treatments, positioning India as one of the leading countries in the international stem cell tourism market. [ 15 ] Despite existing regulations such as NGSCR 2017, the Drugs and Magical Remedies Act of 1954, and recommendations from the ICMR, clinics, and hospitals continue to disseminate misleading marketing materials for purported drugs and magical cures, which is expressly prohibited. [ 12 ]

The underreporting of adverse events (AE) in experimental SCT is a significant concern. There are numerous documented cases of risks resulting from unexpected reactions to these therapies worldwide. [ 16 ] In India, there is a substantial lack of reported cases of AE after SCT, unlike the US, EU, and Japan, where adverse effects, including deaths, have been documented.

In contrast to pharmaceutical drugs, which only provide temporary relief, stem cells can integrate into damaged tissues and facilitate the regeneration of healthy cells thus SCT can be long-lasting and even irreversible in some cases. Nevertheless, further research and follow-ups are needed beyond the recommended NGSCR 2-year follow-up period to ensure the safety and effectiveness of SCT. Figure 2 briefly outlines the factors that contribute to unproven SCT in India.

To ensure responsible innovation and protect patient interests, it is crucial to address regulatory challenges and compare regulations with those of developed nations.

COMPARATIVE ANALYSIS WITH DEVELOPED NATIONS

In the US, the Food and Drug Administration (FDA) governs RM under 21 Code of Federal Regulation (CFR), Part 1271, categorizing stem cell products into 351 and 361 groups. Category 351 products require FDA premarket approval for nonhomologous use, while Category 361 products, intended for homologous use, undergo premarket review without premarket approval. The FDA released a guideline in February 2019 titled “Expedited Programs for RMs Therapy for Serious Conditions,” highlighting the expedited programs available to sponsors of RM for serious conditions. RM advanced therapy is an FDA-approved drug designation for RM aimed at treating serious or life-threatening conditions. [ 17 ]

Similarly, the EU regulates SCT through the European Medicines Agency (EMA) and its Advanced Therapy Medicinal Products law, primarily for more than minimally manipulated products used in nonhomologous situations. While minimally manipulated autologous stem cells are protected under national human tissue laws. In the EU, there is a program called the “compassionate use program,” which is regulated by Article 83 of Regulation (EC) no 726/2004. This program allows patients to access new drugs and biological products, including stem cell products, outside of premarket clinical trials. In addition, stem cell products can receive “conditional market approval” when Phase III trial data collection is nearly finalized. Unlike the US, EMA has implemented another program “hospital exemption” for stem cell interventions. This program allows doctors to administer cellular medicinal products to individual patients in hospitals in Europe under their exclusive professional responsibility. [ 18 ]

In Japan, the RM Promotion Act (RMPA), overseen by the Pharmaceuticals and Medical Devices Agency, promotes the development and use of RM. [ 18 ] This act outlines regulations on manipulation, distinguishing between artificial and minimal manipulation, and excludes certain medical procedures. The RMPA provides conditional market approval for stem cell products after early-phase clinical trials, restricted to qualified medical institutions with postmarketing studies for up to 7 years to ensure the safety and efficacy of the products.

CONDITIONAL APPROVAL AS A NEW APPROACH FOR STEM CELL THERAPY

Developed countries have implemented novel regulatory approaches for SCT by categorizing it based on the level of manipulation involved, to determine the extent of necessary regulation. They have also introduced conditional approval mechanisms to strike a balance between promoting innovation and ensuring patient safety. Nonetheless, conditional approval procedures could lead to unsafe treatments. To address this, EMA has updated its “guidelines for safety, efficacy, follow-up, and risk management.” Similarly, the FDA has created a “guideline for long-term follow-up of gene therapies.” Both countries emphasize the importance of robust postmarket surveillance for RM to ensure transparency and safety.

While countries such as the US, the EU, and Japan have well-defined systems for classifying SCT based on manipulation level and intended use, India’s regulatory landscape for SCT is relatively nascent and lacks standardized categorization. India lacks stringent regulations mandating follow-up studies after compassionate approval, which may lead to a proliferation of unproven practices and pose risks to patient safety. Following the developed nation’s efforts, India must implement postmarketization follow-up studies and risk minimization measures to ensure the safety and efficacy of SCCPs. A comparison of SCT regulation and expedited approval programs in the US, EU, Japan, and India is provided in Table 1 .

PUBLIC EDUCATION AND AWARENESS IN STEM CELL RESEARCH

Alongside addressing regulatory loopholes, the Indian Government needs to take proactive measures to educate its citizens about the advantages and risks of SCT given the country’s low literacy rate. ICMR has released the document “Evidence-Based Status of SCT for Human Disease 2021” to inform the public, patients, and medical professionals about the current state of SCT for various human diseases. In addition, further comprehensive efforts are required. Health regulatory authorities, such as CDSCO and state medical councils, can initiate public awareness campaigns to prevent patient exploitation by updating instructions and increasing awareness. The availability of accessible educational resources and the introduction of stem cell counselors can facilitate informed decision-making. [ 19 ] It is imperative to have collaboration between stem cell counselors, patient advocacy groups, and researchers to provide up-to-date information. Patients should be made aware of the limitations of online information and advised to seek advice from medical professionals.

FUTURE DIRECTIONS AND RECOMMENDATIONS

The RM market is expected to exceed $22 billion by 2027, and India is well-positioned to excel in SCT due to its strong position as a major pharmaceutical producer. However, India also experiences a significant cancer burden, along with cardiovascular conditions and injuries, leading to high health expenditures. The need for affordable and effective treatment options is urgent, and SCT shows promise in reducing financial and health burdens. [ 20 ] The need for affordable and effective treatment options is now more urgent than ever. SCT shows promise in reducing these financial and health burdens, but funding is needed to increase demand and reduce costs for wider accessibility.

Key actions must be taken to ensure the safe and effective regulation and implementation of SCT. (1) India’s regulatory bodies should work together to develop legislation enforcing SCT guidelines with clear definitions and stringent enforcement mechanisms. (2) Three distinct sets of guidelines should be established for researchers, corporate manufacturers, and clinical stem cell therapists. (3) The regulatory bodies should research compassionate approval regulations for developed countries and develop clear regulations for conditional approval of SCT, aligning with international standards and ethical implications. (4) The establishment of a national registry to oversee and regulate stem cell research activities is recommended. This registry would document projects, clinical trials, and outcomes, serving as a platform for data sharing. (5) Need to raise awareness of public stem cell banking by fostering collaboration between physicians and DATRI, India’s biggest database for unrelated blood stem cell donors (6) Health-care providers and researchers must consistently monitor and track AE in SCT, documenting side effects. Implementing clear guidelines and procedures for AE reporting can help assess the safety and efficacy of SCT. (7) Finally, media and health workers should disseminate accurate information about SCT through various channels, addressing public concerns, and engaging with communities to tailor communication strategies and increase acceptance and trust in these therapies. The implementation of these recommendations will promote the safe and ethical adoption of SCT in India, building public trust.

The growing RM market presents significant opportunities for India’s stem cell interventions. However, India needs robust regulation with legal backing, similar to developed countries, to avoid malpractice and ensure safe and effective therapy. While the Indian Government’s compassionate use of SCT holds promise for critical patients, postmarket surveillance is necessary to demonstrate its safety and effectiveness. Collaboration between stakeholders, including industry, academia, and regulatory bodies, is crucial to ensure patient safety and responsible use of SCT. With government support, collaborative efforts, and strategic vision, India can significantly advance SCT while prioritizing patient well-being.

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We gratefully acknowledge the support we received while writing this review from Shri Ramswaroop Memorial University in Barabanki, Uttar Pradesh, India.

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Beyond Student Factors: a Study of the Impact on STEM Career Attainment

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• Published: 17 June 2020
• Volume 3 , pages 368–386, ( 2020 )

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• Tuba Ketenci   ORCID: orcid.org/0000-0002-1665-9884 1 ,
• Audrey Leroux 2 &
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A Correction to this article was published on 28 July 2021

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Despite great institutional efforts to recruit students, including those from underrepresented groups, into the science, technology, engineering, and mathematics (STEM) pipeline, the number of students choosing STEM-related careers remains low. Using data from the Educational Longitudinal Study, we estimated a two-level model of high school sophomores’ choice of STEM-related careers with gender, math self-efficacy, socioeconomic status (SES), school type, and urbanicity as predictors. Our findings show that notwithstanding the obvious private school advantage for attaining a STEM career, attainment is still lower for female students with high math self-efficacy. The gender gap persists among private and public schools regardless of students’ math self-efficacy level. Students are significantly more likely to choose a STEM-related career if they are male in a private school with high SES and math self-efficacy. School urbanicity is also a significant predictor for students having a STEM-related career. We discuss this study’s implications and future research directions.

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• September 19, 2024

In the world of cryptography, both innovation and impact matter. To measure the latter, organizations such as the International Association for Cryptologic Research (IACR) in recent years have established Test-of-Time Awards, selecting winners based on a consensus view of a paper’s lasting impact on the field. At Crypto 2024, held in Santa Barbara, August 18-22, the IACR recognized NTT Research Cryptography & Information Security (CIS) Lab Director Brent Waters with a Test-of-Time Award for a seminal work presented at Crypto 2009.

This is Waters’ sixth such award. Waters received two others from the IACR for Crypto 2008 and EuroCrypt 2005 papers. He also has received two from the Association for Computing Machinery (ACM) and another from the Institute of Electrical and Electronics Engineers (IEEE). In his Crypto 2009 paper, Waters introduced a novel “dual-system” approach to adaptive security for Identity-based Encryption (IBE). (In adaptive security scenarios, adversaries can interact with systems and adapt their strategies accordingly.) Waters’ approach was soon thereafter expanded to include Attribute-Based Encryption (ABE) – ABE being another of his ground-breaking contributions to the field – and more. Waters was the sole author of the Crypto 2009 paper and served as a key co-author on the other five Test-of-Time Award-winning papers. Over his career, he has also received numerous Best-Paper Awards, which are presented when papers are delivered.

Waters, who is also a professor at the University of Texas, Austin, has been instrumental in building the CIS Lab team into one of the world’s preeminent cryptography organizations since assuming the director’s role in 2022. At Crypto 2024, Waters and six other cryptographers affiliated with the CIS Lab presented 12 papers. The CIS Lab typically leads other research organizations and universities in terms of accepted papers at top-tier conferences.  Combined with eight papers from colleagues at the NTT Social Informatics Laboratories (SIL), a division of NTT R&D, the total NTT contribution was a significant percentage of the 143 total papers accepted at Crypto 2024.

Key to the CIS Lab’s success has been assembling a critical mass of top theoretical cryptographers. The field itself is a specialty, existing at the crossroads of mathematics and computer science. “Even if you look at top universities, the cryptography group will maybe be one or a couple of people,” CIS Lab Senior Scientist Elette Boyle said at the NTT Research Upgrade 2024 event. “Here we have a powerhouse. And I think even just having everybody there together, the interaction, you walk down the hall, you ask the world expert some question about something and then you start chatting over coffee and you start developing one of the next directions of research that can really lead to a next big thing.”

These internal dynamics among the ten current members of the CIS Lab have been augmented by external collaboration that includes research agreements, internships, post-doctoral fellowships and a visitor program. As another indicator of its influence, for instance, the “Best Paper Authored by Early Career Researchers” award at Crypto 2024 was co-authored by Aajush Jain, a former CIS Lab post-doctoral fellow.

One additional superpower is the CIS Lab’s link to industry. While focused on basic research, in cases where a given scientific and technological innovation has matured to the point of meeting a market demand (as with ABE), NTT Research is positioned to collaborate with other divisions of NTT – such as NTT R&D, NTT DATA, etc. – and real-world customers to further test, develop, and deploy potential solutions.

All the same, there is no mistaking the theoretical nature of this field, as evidenced by the dense mathematical arguments found at the heart of any given paper. Nor can you escape the critical role of theory that theory plays. Looking ahead, Waters said at Upgrade 2024 that one goal on his research agenda is to revisit an effort from the 1980s to make the “hardness” assumptions of cryptographic theory smaller, or more believable. (Hardness relates to the degree of difficulty in solving a particular problem.) In the end, the firmer the cryptographic foundation, the higher you can build.

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Office:  Vehicle Technologies Office

FOA number:  DE-FOA-0003344

Link to apply:  Apply on EERE Exchange

FOA Amount: $72 million

The U.S. Department of Energy (DOE) announced the SuperTruck Charge funding program, which will award $72 million for projects that will enable the design, development, and demonstration of innovative electric vehicle (EV) charging infrastructure near key ports, distribution hubs, and major corridors in support of electrified medium- and heavy-duty vehicles (MHDVs). SuperTruck Charge seeks innovative and replicable solutions supporting medium- and heavy-duty (MHD) EVs, accelerate charging infrastructure deployment, and reduce greenhouse gas (GHG) emissions. 

There is a need to identify large scale replicable high power charging installations to serve MHD electric fleets with tens to hundreds of vehicles. There is also a need to develop high-capacity charging infrastructure to serve MHD electric trucks for long-haul use cases (more than 500 mile per day) along major corridors and rural regions where grid capacity is limited. 

The United States recently signed the Drive to Zero Memorandum of Understanding , which sets the ambition of having 30% of all new MHDV sales be zero emission by 2030 and a full transition to zero emission fleet by 2040. Further research, development, and demonstration of high-capacity high-power charging installations with Vehicle Grid Integration (VGI) strategies for electrified MHDVs will be critical to meet these goals while ensuring equipment interoperability, mitigation of grid impacts, improving grid resiliency and reliability, and creating downward pressure on electricity rates. 

This funding opportunity identifies potential solutions to address the current gaps in electrified MHDV charging infrastructure necessary to enable greater utilization of electrified fleets, and drastically reducing GHG emissions due to MHD trucks. This program encourages the development and inclusion of innovative wired and non-wired charging solutions to deploy high power electric vehicle charging for MHD EV fleets. The outcomes of this program will lead to accelerated deployment of large-scale public electric vehicle charging infrastructure with clean energy resource technologies, as well as provide greater grid resiliency and reliability. SuperTruck Charge is aligned with the U.S. National Blueprint for Transportation Decarbonization plans and strategies to address energy justice, fuel the economy, create good paying jobs, and expand access to cutting-edge technologies that reduce GHG emissions and create healthier communities.

VTO expects to make two to three awards under SuperTruck Charge, each ranging between $24 million and $36 million. 

As part of the application, applicants are required to describe how diversity, equity, and inclusion objectives will be incorporated in the project. Specifically, applicants are required to submit a Diversity, Equity, and Inclusion Plan that describes the actions the applicant will take to foster a welcoming and inclusive environment, support people from groups underrepresented in STEM, advance equity, and encourage the inclusion of individuals from these groups in the project; and the extent the project activities will be located in or benefit underserved communities. Applications must also ensure that proposed charging infrastructure deployments are open to multiple fleets and/or provide a public charging aspect to demonstrate broader access and utilization.

Prior to submitting a full application for this opportunity, a mandatory concept paper is due on October 8, 2024 at 5:00 PM ET. 

Funding for this FOA is subject to congressional appropriations.

Topic Areas

• Subtopic 1a - Innovative Depot Charging Infrastructure Design and Development to Support Electrified MHDVs Near Hubs, Ports, & other Logistics Operations: The objective of this subtopic is to research, develop, and demonstrate concepts for meeting the necessary charging needs for Class 6-8 electric truck fleets charging at hubs, ports, and other logistical operations
• Subtopic 1b - High-capacity Charging Infrastructure Design and Development to Support En-route and Long-haul Electrified MHDVs Along Major Corridor:  The objective of this subtopic is to research, develop, and demonstrate concepts for medium- and heavy-duty Class 6-8 electric truck charging installations along major freight corridors (as defined by the U.S. Department of Transportation, Federal Highway Administration).

Additional Information

• Download the full funding opportunity  on the EERE Exchange website.
• For FOA-specific support, contact  [email protected] .
• Sign up for the Office of Energy Efficiency and Renewable Energy (EERE) email list  to get notified of new EERE funding opportunities. Also sign up for the VTO GO! newsletter  to stay current with the latest VTO news.

• Open access
• Published: 08 September 2021

Engineering practices as a framework for STEM education: a proposal based on epistemic nuances

• Cristina Simarro   ORCID: orcid.org/0000-0001-8532-0879 1 &
• Digna Couso 1  

International Journal of STEM Education volume  8 , Article number:  53 ( 2021 ) Cite this article

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The role of engineering education has gained prominence within the context of STEM education. New educational perspectives such as the National Research Council’s Framework for K-12 Science Education consider engineering practices one of the central pillars of a sound STEM education. While this idea of developing a set of practices analogous to those of professional engineering resonates with recent views of STEM education research, current approaches such as the NRC’s Framework seem too dependent on and interlinked with the list for scientific practices and adheres to this list too strictly. This paper draws on the NRC’s Framework proposing a new set of engineering practices that seek to incorporate the epistemic nuances that differentiate engineering from science. The nine engineering practices proposed contain epistemological nuances that are missing in other proposals, including essential aspects such as problem scoping, identifying multiple solutions, selecting, testing and improving solutions and materializing solutions. This epistemic approach may facilitate students’ content learning and thinking development, offering a more comprehensive and realistic view of the STEM fields.

Introduction

The advocacy for STEM education has been pervasive in current educational debates. There is no doubt that the idea of giving relevance to Science, Engineering, Mathematics and Technology, whether integrated or not, has marked the direction of many educational policies and has been a topic of interest in the field of education research (Bybee, 2013 ; Johnson et al., 2020 ). Within this approach, and influenced by the perspective of design as a new twenty-first century literacy (Blikstein, 2013 ; Pacione, 2010 ), the role of engineering education has been modified, gaining more prominence and centrality in pre-college education (Li et al., 2019 ; Pleasants & Olson, 2019 ). This new role of engineering in the education-for-all perspective is exemplified in the Framework of the National Research Council ( 2012 ) where a prominent place is given to engineering. In this framework, reflecting the importance of understanding the human-built world and recognizing the value of better integrating the teaching and learning of science, engineering, and technology are the reasons behind the elevation of engineering design to the level of scientific inquiry.

Some authors argue that engineering education can improve students' learning in science and mathematics (by providing, for example, a context in which to test scientific knowledge and apply it to practical problems), increase knowledge of engineering and the work of engineers, increase students' technological literacy, and stimulate young people's interest in pursuing engineering as a career. In relation to the idea of STEM education and the integration of its disciplines, there are those who believe that engineering education can act as a catalyst for more interconnected STEM education (King & English, 2016 ; National Academy of Engineering & National Research Council, 2009 ; National Research Council, 2012 ). However, critical voices have denounced the mismatch between the call for more and better engineers and the low presence of engineering education in compulsory education, especially in primary and lower secondary (Bagiati et al., 2015 ; Lucas et al., 2014 ).

In our opinion, some of the motivations and potential benefits of enhancing the presence of engineering in pre-college education somewhat undermine the true raison d'être of this engineering education, which would, in turn, explain the shortcomings pointed out when it comes to engineering education. For instance, the perspective of engineering as a context is fundamentally based on an idea of education focused on the products of engineering as a discipline (e.g.: energy and power technologies). Frameworks such as those of Science, Technology and Society (Bybee, 1987 ) are based precisely on this perspective, where relevance is given to technology (the product of the engineering activity) and not to the engineering practices themselves, emphasizing the connection with other disciplines. Similarly, when technology and engineering are placed at the heart of an integrated STEM education there is an imbalance in the focus on the different STEM disciplines (Honey et al., 2014 ), with engineering and technology often gaining more centrality (Becker & Park, 2011 ) and science and mathematics being used as contexts or tools for tackling technological design problem-solving (English, 2016 ; Sokolowski, 2018 ).

As a result, current STEM education tends to focus on the use of technology per se instead of promoting a way of intervening in relevant social contexts. Hence, engineering and technology education, and STEM education as a consequence, has been criticized for offering a techno-centric view where, for instance, the use of creative technologies is the main concern (a distorted understanding of the T in STEM, identified only as computing (Sanders, 2009 )). This approach moves away from a literacy perspective of STEM education for all and tends to alienate some profiles that are expected to be attracted to STEM disciplines, and especially to engineering, such as girls (Moote et al., 2020 ).

In consequence, there is a growing consensus that engineering education should follow the example of science education by engaging students in disciplinary practices (Cunningham & Carlsen, 2014a ; National Research Council, 2012 ), that is, engage them more in its processes than in its products. Recognizing engineering as a cognitive, social and cultural activity (Bucciarelli, 2003 ) implies recognizing that it encompasses specific practices, that is, specific ways of doing, talking, thinking, valuing and being (Couso & Simarro, 2020 ). From this sociocultural perspective of education, in the same way that scientific practices are seen as a core content for science education (Duschl & Grandy, 2013 ; Osborne, 2014 ), the participation of students in school-based engineering practices analogous to those of the professional engineering world becomes a central element of 21st engineering education.

From engineering process to engineering practices

Seeking to help young students engage in engineering design as a new literacy (English & King, 2015 ), several design and engineering design process models have been recently developed in formal and non-formal contexts, specifically for young grades (primary and lower secondary) (Dorie et al., 2014 ; English & King, 2015 ). While based on an old-fashioned step-by-step approach, and hence far from the idea of learning engineering as participating in a complex and rich cultural practice, it is interesting to identify similarities and differences between these processes. Table 1 summarizes some of these engineering processes, highlighting commonalities and divergences.

Most of these models, for instance, include the idea of scoping the problem, defining the constraints and criteria to bear in mind. While relevant in solving engineering problems in the workplace, little attention is usually given to this engineering activity, especially for young learners (Dorie et al., 2014 ). According to research, problem scoping differentiates experts from novices, with the former spending more time engaged in this type of activities that may lead to higher-quality engineering design solutions (Atman et al., 2007 ). Problem scoping may entail, among others, clarifying and restating the goal of the problem, identifying constraints to be met, exploring feasibility issues and drawing on related context to add meaning (English & King, 2015 ).

Some of the models of the engineering process also refer to the existence of more than one possible solution which entails the need for a selection process based on the defined criteria. This selection process includes the consideration of what others have done to solve the problem, including prior research, and brainstorming for generating new ideas for solutions (NASA, 2009 ). The idea of building a prototype for testing is also present in some of these engineering processes. In contrast to the idea of a descriptive or interpretative model, which is used to demonstrate or explain how a product will look or function, a prototype is used to test different working aspects of a product before the design is finalized (TeachEngineering, 2009 ). Prototyping is considered an activity undertaken by informed designers, and that is an essential part of the design process (Crismond & Adams, 2012 ). Finally, only two of the models refer to the need to communicate, understood as an essential activity for conveying how the solution solves the identified need or problem and meets the criteria and constraints (Massachusetts Department of Elemantary & Secondary Education, 2016 ).

Regardless of the degree of completeness with which the steps included in the different versions of the engineering process summarized in Table 1 are followed, the main problem that we see in common in all of them is that they are focused to sequence a process that can be applied to solve any problem (even those which are not from engineering). Hence, they lack an approach that sees engineering not only as a single set of procedures but as an idiosyncratic and complex cognitive, social and discursive cultural activity with its own tools and rules. The eight engineering practices proposed by the National Research Council ( 2012 ) go one step beyond the idea of engineering process to present engineering as the participation in a set of practices which require the simultaneous coordination of both knowledge and skills:

Defining problems

Developing and using models

Planning and carrying out investigations

Analyzing and interpreting data

Using mathematics and computational thinking

Designing solutions

Engaging in argument from evidence

Obtaining, evaluating, and communicating information

Despite the crucial paradigm shift that entails viewing the teaching and learning of engineering not as the mastery of a generic problem-solving approach but as the promotion of active student participation in engineering practices, we consider the NRC engineering framework insufficient. The main reason is that the list of practices are too dependent on and interlinked with the list for scientific practices: only two practices are specific to engineering (defining problems and designing solutions) while the rest are exactly the same for both science and engineering. In this regard, and from an epistemic viewpoint, we strongly disagree with authors, such as Bybee ( 2011 ), who claim that with the exception of their goals, science and engineering practices are parallel and complementary. As Cunningham and Carlsen ( 2014b ) argue, we believe that a subtle differentiation between science and engineering does not capture the epistemic differences between the two disciplines, and thus does not reflect certain salient engineering values that are essential to the engineering discipline and, at the same time, differentiate it from other disciplines (Couso & Simarro, 2020 ).

Surprisingly, if a complete reading of the NRC framework is made, some of these differences can be grasped. For example, when discussing models, the framework introduces the concept of the prototype as a key element in engineering (as it occurred in the engineering processes compared above). From this perspective, one can evaluate the different role that the model idea plays in both disciplines: for science, a model is a key element and is part of the final product of its practice, whereas in engineering, a model is a tool to test a simplified version of the solution before its final release. A scientific model is a conceptual structure that represents a phenomena in order to describe, predict and explain it (Oh & Oh, 2011 ). As such, it is a reasoning artefact which is the product of the practice of modelling (Couso & Garrido-Espeja, 2017 ). An example is the Bohr model of the atom, which can be expressed in terms of drawings, written accounts, physical models (such as a play dough one) and others. Conversely, an engineering model (prototype) is intended to describe systems to be built and has evaluation as its primary objective (Combemale et al., 2016 ; Jensen et al., 2016 ). Small scale constructions or alpha versions in software developments are some examples of prototyping in engineering. Similarly, the importance of optimization in engineering is also emphasized, highlighting the existence of multiple solutions to the same problem and the selection of one based on a balance between the constraints and specifications defined in each case. While not labelled as optimization, this idea is also present in the step-by-step approaches to the engineering method reviewed previously. In contrast, science is always looking for the simplest and most explanatory solution, with the goal of science being to find a single theory that applies in a complete and coherent way to a large number of related phenomena. This fact also involves differences at the level of argumentation made by scientists and engineers: while in the first case the argumentation seeks to rule out possible alternative explanations based on multiple tests, in the second the main thing is to justify the choice made, evaluating prospective designs and producing the most effective design to meet specifications and constraints (National Research Council, 2012 ).

Despite the differentiation made in the text, the list of eight engineering practices proposed in the NRC curriculum framework do not sufficiently emphasize the important differences between both disciplines, science and engineering (Cunningham & Carlsen, 2014a ), and their statements, built in the image and likeness of scientific practices, do not encapsulate key elements of the nature of the engineering activity. Given the relevance that the list of eight engineering practices has on educational standards and curriculum designs, we consider the need for a new conceptualization of engineering practices in which the idiosyncratic differences between science and engineering are reflected. This is not to avoid an interdisciplinary STEM teaching approach where both science and engineering are considered, but to help teachers to improve students’ understanding and knowledge both of and about engineering either in disciplinary or interdisciplinary oriented curricula.

Including epistemic nuances to the idea of engineering practices

A rich engineering education that educates not only in engineering but also about engineering needs to entail an epistemic view of the discipline, that is the range of practices, methodologies, aims and values, knowledge and social norms that characterize the disciplines (Erduran & Dagher, 2014 ). In this regard, and as we have published elsewhere (Couso & Simarro, 2020 ), STEM education would strongly benefit from taking an epistemological perspective that emphasizes the differences between science and engineering, in order to better understand the relationship and inter-dependence between both disciplines.

Table 2 summarizes main epistemic differences between science and engineering disciplines (Couso & Simarro, 2020 ). Without going into detail, we highlight here some of these differences. Regarding their Aim , which can be considered the main distinctive characteristic between disciplines (Park et al., 2020 ; Sinclair, 1993 ), science and engineering pursue goals of a distinct nature. Science focuses on developing theoretical descriptions and constructing reliable explanatory frameworks of the natural world in order to understand and act upon it. Engineering has as a primary aim the construction of optimal human-made solutions. Hence, engineering objects of knowledge are human-made artefacts, including their study in functional terms and their construction (Boon, 2006 ; Bunge, 2017 ; Hansson, 2007 , 2015 ; National Research Council, 2012 ; Sharp, 1991 ). The different nature of the aim of each discipline entails that while engineering solutions need to be concrete, operational and feasible today, a scientific explanatory framework such as a theory or model can only be abstract and conceptual. Furthermore, despite the evidence-based nature of models or theories, their connection to reality can be researched much later than their theoretical envisioning. Derived from each discipline’s aim, different Spheres of Activity are identified for science and engineering that follow their respective aims. Scientific activity is characterized by three interconnected fields of action that involve the socio-discursive and reasoning processes of: inquiry, argumentation and modelling (Duschl & Grandy, 2013 ; Osborne, 2014 ). Engineering practices take place in the creation (problem scoping and solution generation), the evaluation (assessment and selection) and the realization (making and bringing ideas to life) spaces (Dym et al., 2005 ).

These core activities result in specific scientific and engineering Forms of Knowledge. Principles, theories, laws, models and facts are recognized forms of knowledge that work together in generating and validating scientific explanations (Erduran & Dagher, 2014 ) while mechanisms, processes and technologies could be understood as the way knowledge is encapsulated in engineering, both as a source and product of the engineering activity. Although less work has been done regarding the nature of engineering in order to establish the forms of knowledge that are important for this field, many authors agree on considering that engineering generates knowledge for use in design, thus related to specific technologies: how particular technologies function, analytical tools and models that can be applied to a range of technological phenomena,… (Pleasants & Olson, 2019 ; Vincenti, 1990 ). Values and Quality Criteria are again specific aspects that characterize science and engineering. The descriptions and interpretations constructed by science intend to be accurate, universal, simple, coherent, mutually consistent and based on evidence in an adequate, valid and reliable way. Therefore, scientific explanatory, descriptive and predictive frameworks are successful as far as they are adjusted to these values (even theoretically) regardless of their immediate practical application. In contrast, engineering values are closely connected to the practical feasibility and success of the engineered solution. Success is measured by the extent to which a technical solution provides an answer to a problem addressed in an optimal way, in terms of applicability, reliability, effectiveness and efficiency (Boon, 2006 ; Erduran & Dagher, 2014 ; National Research Council, 2012 ).

Finally, and influenced by the characteristics of other dimensions, both science and engineering follow specific Methodological Rules that meet these values and quality criteria. In science, these methodological rules basically refer to the sophisticated ways in which theory, data and evidence should be coordinated. For engineering, where there is less room for idealization, other methodological rules apply. Of particular importance is the need for actual testing of the diverse proposed solutions (Hansson, 2007 ; National Academy of Engineering & National Research Council, 2009 ).

All these dimensions—spheres of activity, forms of knowledge, values and quality criteria, and methodological rules—influence the more visible and recognizable characteristics of science and engineering. Science and engineering Practices, Knowledge, Ethos and Methods are the characteristics of the disciplines that are more context-dependent and, as such, less idiosyncratic. In this regard, some overlap exists in the way we define these characteristics in different disciplines which could explain, for instance, the interdependence between scientific and engineering practices proposed by the NRC framework and evident in the many fields that combine both, such as nanotechnology or bioengineering.

Towards a more comprehensive account of engineering practices

Several voices have identified the lack of epistemic emphasis on the engineering PreK-12 standards and the imbalanced presence of disciplines in STEM education (Cunningham & Carlsen, 2014a , 2014b ; ITEEA & CTETE, 2020 ). As a result, new educational proposals have recently been emerging. A clear example is the new Standards for Technological and Engineering Literacy developed by the International Technology and Engineering Educators Association (ITEEA) and the Council on Technology and Engineering Teacher Education (CTETE) ( 2020 ). These new standards acknowledge the epistemological basis of engineering and technology and propose a new framework which also includes engineering (and technological) practices as one of its organizers. However, while these practices are seen as key attributes and personal qualities that all technology and engineering students should exhibit, they are, in our opinion, more based on the idea of skills and competences (e.g.: collaboration, communication, creativity…) rather than on the discipline’s spheres of activity that characterize the NRC idea of practices.

In this regard, while recognizing the shortcomings of the NRC engineering practices highlighted before, we draw on them to propose a new set of engineering practices that seek to incorporate the epistemic nuances discussed above. Bearing in mind these epistemological differences, especially in terms of spheres of activity, as well as the approaches that address to some extent the idea of ​​engineering process (Table 1 ), we propose a set of nine engineering practices that emphasize some of the key elements that, from our point of view, should be included in the idea of engineering practices (Table 3 ).

What follows is a summary of the main ideas included in our proposal. Their description does not follow the order of the practices as presented in the NRC’s framework but is based on the nature of the proposed changes: for some practices a new definition has been proposed or expanded (e.g.: defining problems and designing solutions), while for others only some concepts have been nuanced (e.g.: models vs. prototypes or simulations and investigations vs. tests) or have been even integrally kept (engaging in argument from evidence and obtaining, evaluating, and communicating information).

From defining problems to defining and delimiting problems

Expanding the idea of problem definition, this proposal highlights the need for delimiting problems, that is, establishing what constraints need to be considered when thinking about possible solutions. Hence, Defining Problems practice becomes Defining and Delimiting Problem s which, in fact, is already stated as one of the engineering core ideas, including the emphasis given to this core idea of specifying clear criteria within the practice itself. Delimiting includes the concept of systems thinking because it limits the scope and allows definition of the restrictions and the criteria of success. In our opinion, this way of defining a problem, including its explicit delimitation, is not trivial since “Many such problems (to which engineers are invited to solve) (…) are ill-defined or wicked problems, meaning that it is not at all clear what the problem is exactly and what a solution to the problem would consist in” (Franssen et al., 2018 ). Moreover, the idea of delimitation suggests the need to consider a holistic approach to engineering problem-solving, presented as an open system that requires considering all aspects and perspectives not only of artefacts and users, but also their effects on the environment, individuals, and society and culture (Karatas et al., 2011 ). As Hansson ( 2007 ) points out, engineering often deals with concepts loaded with value such as user-friendliness, respect for the environment, or risk. This problem framing is seen by research as a crucial difference between experienced and novice designers (Crismond & Adams, 2012 ), influencing the entire design process.

As an example, beyond asking students to define the problem to be solved (what is needed, what is the purpose, what are the functions that a solution must accomplish…) we ask them to bear in mind the context in which the problem takes place. This may entail considering constraints related to sustainability and economy, understanding end-users’ characteristics or assessing resources at hand. Allowing students to assess the suitability of existing solutions, considering several constraints, could help students in elementary levels to start thinking beyond intrinsic solution variables as constraints while more advanced students could be faced with complex contexts in which they identify nonobvious needs or constraints.

From designing solutions to identifying and/or developing multiple solutions and selecting the optimal one

In regard to the idea of designing solutions, the practices proposed by the NRC present, from our point of view, a fundamental problem, also applicable to scientific practices. In our opinion, the idea of designing solutions (for engineering) or building explanations (for science) is too generic as a practice and, in fact, is basically the goal (aim) of each discipline as we have previously discussed. Looking to offer an alternative that includes some of the key aspects highlighted for engineering, in our proposal we have raised the idea of identifying and/or developing multiple solutions and selecting the optimal one . This specification is based on the understanding that, in engineering, solutions are never unique and that only by considering the constraints posed in the delimitation of the problem (and from a holistic perspective as discussed above), can one choose a desired solution to consider and to bet on, for example, the realization of prototypes and tests.

With elementary students this practice can be developed by comparing existing solutions to a similar need (for instance, comparing electric cars with internal combustion engine vehicles or diverse heating systems) and discussing according to which constraints each solution would be optimal. Higher level students may define their own solutions and compare them with others to finally decide which is the best solution given specific constraints and considering trade-offs among them. The objective is to see that diverse solutions are possible but only few of them offer trade-offs levels that make them eligible. Developing this practice with students and embracing their different solutions to the same problem helps to enhance the epistemic idea that there are multiple solutions to the same engineering design problem and that the optimal solution can change depending on the criteria and constraints considered.

From using mathematics and computational thinking to including scientific models and available technologies

Similarly, and regarding the practice of using mathematical thinking and computational thinking, our proposal adds two ideas that would also be useful for scientific practices: the use of scientific models and available technologies . According to this, both the results of the scientific (models) and engineering (technologies) activity also serve as a resource to achieve each of the respective aims of both disciplines. This approach is more in line with the idea of STEM as a field in which their disciplines share common grounds and are profoundly interrelated, despite not being the same. Moreover, and in the case of engineering, it acknowledges how understanding the natural world may help engineering processes and technologies to improve and make visible the nature of technology as an evolution and combination of previous technologies (Arthur’s combinational evolution (Arthur, 2011 )).

Developing this practice among students should encompass the analysis of the evolution of current technologies, understanding how scientific advances explain technology transitions as well as identifying which technologies enabled the conceptualization of new solutions (for example, how radio wave communication revolutionized global communication systems). Older students should also take advantage of their scientific, technological and mathematical knowledge to define and optimize their own solutions.

From models and investigations to prototypes, simulations and tests

Additionally, our proposal adds nuance to some of the words commonly used for scientific and engineering practices. On the one hand, with regard to models, there has been an attempt to avoid confusion with the idea of scientific model because we believe that the “models” used in engineering (to test possible solutions and to look for points for improvement) differ greatly from the idea of scientific models. Thus, we propose the terms prototypes and simulations , following some of the curricular proposals presented above. On the other hand, there has also been an attempt to avoid the use of the word investigation which could be easily linked to the idea of inquiry . Given the relevance of this concept of inquiry for science teaching we alternatively propose to talk about testing. Beyond a trial-and-error approach, engineering testing also requires a thoughtful plan, considering the variables to be considered for answering the posed questions. However, while science investigations seek to obtain evidence for confirming existing theories and explanations or to revise and develop new ones, engineering tests aim to validate the performance of a solution given specific constraints. Hence, while scientific inquiry uses evidence for assessing the world of ideas, engineering tests obtains evidence from and to the world of objects.

From analyzing and interpreting data to identifying points of improvement

Seeking to emphasize the idea of ​​optimization, so relevant to engineering, the practice of analyzing and interpreting data has been nuanced with the identification of points for improvement , considering the need to respond to the constraints identified in delimiting the problem. As discussed above, engineering solutions are less idealized than scientific explanations. In this regard, the best engineering solution is charged with diverse values beyond its efficacy, which influence a diverse number of trade-offs to be assessed and tackled before confirming the suitability of the solution. Hence, the analysis and interpretation of data is made in light of this optimal solution and not only to see if data obtained through engineering test confirm whether a solution is suitable or not.

Engaging in argument from evidence and obtaining, evaluating, and communicating information

The three last practices discussed above (development of prototypes and simulations, planning of tests and analysis for the identification of points of improvement) are those more related to the hands-on nature traditionally linked to technology and engineering as an educational subject. However, these practices are not minds-off. While they usually occur in the world of objects (with tests carried out with physical prototypes or simulations) these practices are also loaded with ideas, including the hypothesis made while defining the tests to carry out. These hypotheses will be linked to the constraints and contexts considered when delimiting the problem. In this regard, beyond activities addressed to prototyping and simulating (with the emerging creative technologies such as 3D printing or block programming solutions) we must present students with activities in which they define the criteria for success and design reliable tests in order to obtain evidence. This evidence and the quality of the conducted tests will in turn be central to arguments used while communicating the suitability of one solution. In our proposal, the practices of building arguments based on evidence and obtaining, evaluating and communicating information have been maintained, as it has not been considered necessary to make any clarifications or add nuance in relation to scientific practices beyond the assumption that both engineering evidences and tests have a different nature to scientific evidences and inquiry processes.

Materialization: a new practice

Finally, our proposal includes a ninth practice, not considered in the NRC list, which involves the idea of non-idealization in engineering solutions: the materialization of the solutions . The challenge of moving from a desired function for a technology to the real structure that will produce that desired function is seen as a mysterious practice that can not be achieved mechanistically or algorithmically but that requires great creativity (Pleasants & Olson, 2019 ). Hence, this ninth practice of materialization seeks to encapsulate this creative but strongly constrained process of grounding the theoretical ideas about the solutions considering the actual technological and socio-economic limits of the context in which the problem is being solved, which include the actual available or affordable resources (e.g.: materials at hand to use in order to have a low environmental or economic impact). This materialization practice focuses not only on the construction of the solutions themselves (bringing them to life, as some authors say) but includes what some authors have called visualization, an engineering habit of mind that refers to the ability to move from the abstract to the concrete, that is, how to concretize an idea to arrive at a practical solution, including the selection and manipulation of real materials (Lucas et al., 2014 ). At this regard, while we agree with Cunningham and Kelly ( 2017 ) that one core feature of potential solutions that must be carefully weighed to the non-ideal solutions of engineering is what materials the technology is made from and consequently that the practice of considering materials and their properties is a core engineering practice, we think that this idea of materialization as a creative process goes beyond materials and encompasses all the concepts or engineering knowledge that may help realizing the solution (including, for instance, the processes to be used). And it is that making and doing are at the heart of what makes technology and engineering so different from other fields, including skills such as manipulating materials and effectively using hand and power tools (ITEEA & CTETE, 2020 ). This materialization practice is a broader practice included in the third sphere of activity in which, according to some authors, the engineering design process takes place: creation, evaluation and realization (Dym et al., 2005 ). Thus, from our point of view, this materialization practice is an important difference between science and engineering, being one of the engineering spheres of activity highlighted above, which is not captured in the eight practices proposed by the NRC’s framework.

Developing this materialization among students goes beyond the construction process itself and must encompass a critical selection, acquisition and treatment of materials and the organisation and participation in the processes to be used when turning student solutions into reality. Younger students must be trained in such practice by critically analysing existing technologies or solutions and discussing if the materials used are the most suitable for the solution’s purpose and considering available resources such as environment (e.g.: comparing diverse plastic water bottles). Older students would face real challenges in which they decide which of the resources at hand could be used for implementing their theoretically designed solution.

Conclusions

PreK-12 engineering education is still under development. While recent efforts such as the inclusion of engineering practices in the NRC Framework ( 2012 ) or the recent Standards for Technology and Engineering Literacy (ITEEA & CTETE, 2020 ) confirm an ascending trend of the role of engineering in STEM education, the truth is that engineering is still commonly underrepresented and misunderstood, particularly in pre-college education for all. In our opinion, this misrepresentation is due to a lack of epistemological view of disciplines, which hinders a rich view of the nature of each of the STEM disciplines (Couso & Simarro, 2020 ; Erduran, 2020 ). In the case of engineering, this imbalance is exemplified in the dependence of the engineering practices proposed by NRC, which are mainly based on disciplines similarities instead of essential disciplinary differences (Cunningham & Carlsen, 2014b ; Cunningham & Kelly, 2017 ).

Our proposal has tried to apply the centrality given by the NRC framework to the idea of practices as the spheres of activity of engineering that we want to analogically develop with our students. While similar work has been done in the same direction, like the suggestive epistemic practices of engineering for education proposed by Cunningham and Kelly ( 2017 ), our proposal has been intended to take advantage of the already existing NRC framework which is influencing many standards and is being integrated by teachers. The nine engineering practices that we have proposed embed the epistemological load that is missed in other proposals, including essential aspects such as problem scoping, identifying multiple solutions, selecting, testing and improving solutions and materializing solutions. In this proposal, design is not only a part of the practices, but the overarching practice linked to the engineering actual disciplinary aim. In our opinion, STEM educators will benefit from the emphasis given to engineering disciplinary idiosyncrasy because it will allow them to promote a sound STEM education that offers a more comprehensive and realistic view of all the STEM fields (Ortiz-Revilla et al., 2020 ). As Li and colleagues argue, educational research would benefit from a better identification, examination, and comparison of specific epistemic practices pertinent to different disciplines in STEM to facilitate students’ content learning and thinking development (Li et al., 2019 ). In the specific case of engineering, epistemic beliefs about engineering (nature of engineering (NOE) views) can influence students’ learning and a better understanding of NOE is a crucial component of engineering literacy (Deniz et al., 2019 ). In this regard, the set of engineering practices presented in this paper seeks to enhance students’ NOE views in order to allow them to better appreciate epistemic aspects of the engineering design process. Being able to integrate practices of the different STEM disciplines is one of the desirable outcomes of a sound STEM education, which would not happen adequately without a clear epistemological approach.

However, the development of engineering practices is only a portion of what a rich engineering education may offer in order to achieve high levels of engineering literacy among students. The development of engineering practices is beneficial not only in terms of the content of the practices themselves, but is also useful for learning other relevant conceptual content such as the central ideas of engineering. In this regard, more work has to be done if we want engineering to have a more prominent status within STEM disciplines not only by adding a technological component or providing interesting “ways of doing”, but also by providing conceptual artefacts and tools to think about the world and act on the world.

Unfortunately, the imbalance between science and engineering is also evident when it comes to the so-called core ideas . Presented in the NRC framework as the key important concepts of each discipline, and following the philosophy of Harlen’s big ideas of science (Harlen, 2010 ), these core ideas are, together with the idea of scientific and engineering practices and crosscutting concepts, one of the three dimensions of the Framework. However, while in the case of science a total of eleven key ideas with their corresponding sub-ideas are included within the scientific core ideas, only two core ideas are listed for engineering, the first being very close to the idea of practice (engineering design) and the second being the interrelation between engineering, technology, science and society. Hence, while identified as core ideas, the truth is that they do not correspond to the definition of a core idea. As Cunningham and Carlsen ( 2014b ) point out regarding the first engineering core idea (ETS1: Engineering Designs) it sounds like activities—defining and delimiting an engineering problem, developing possible solutions, and optimizing the design solution- and not like concepts, principles, or theories. Moreover, the second core idea (ETS2: Links Among Engineering, Technology, Science, and Society) is far from being a central idea of engineering, but is instead a reflection about the relationship between both science and engineering that: (1) is not included in science core ideas, and (2) gives the idea, according to how it is specified, of engineering and technology as a mere application of science (Ortiz-Revilla et al., 2020 ). Again, the effort of equating engineering and technology contents to science content is limited by the lack of an epistemological view.

The new Standards for Technological and Engineering Literacy (ITEEA & CTETE, 2020 ) seek to broaden the concept of engineering core concepts. However, in our opinion, they fail to propose operational dimensions and categories for such core concepts, mixing elements of diverse nature (some related to practices (resources, requirements, trade-off, optimization), other elements related to cross-cutting concepts (system and process) and others more related to specific technologies (control)).

Perspectives about how technologies are developed (including the exploitation of natural resources), their nature (how they are and how they are used) and their applications (in which contexts they are used and the particularities that characterize each context) could be pillars to support a robust framework for defining the missing engineering core ideas.

Finally, our work has been focused on engineering literacy. While the links between engineering and technology are blurred, sometimes leading to discussions about technological and engineering literacy as a whole (ITEEA & CTETE, 2020 ), we believe that some reflection should also be done in order to deepen on the understanding of their differences. As mentioned previously, engineering practices such as the ones proposed in this paper are built under the umbrella of design as the core practice of engineering, related to the engineering aim of constructing optimal solutions. Considering technology as a field that, rather than designing them, uses human-designed products, systems, and processes to modify the natural environment in order to satisfy needs and wants (ITEEA & CTETE, 2020 ), a person literate in technology should perhaps develop specific technological practices which could be linked to, but different from, engineering ones.

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Abbreviations

Science, Technology, Engineering and Mathematics

National Research Council

International Technology and Engineering Educators Association

Council on Technology and Engineering Teacher Education

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Acknowledgements

This work was supported by the Spanish Government Project ESPIGA [PGC2018-096581-B-C21], within the ACELEC research group [2017SGR1399].

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Simarro, C., Couso, D. Engineering practices as a framework for STEM education: a proposal based on epistemic nuances. IJ STEM Ed 8 , 53 (2021). https://doi.org/10.1186/s40594-021-00310-2

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