Category Archives: Stem Cells

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For the first time, scientists have grown miniature models of the human brain that incorporate the organ's built-in security system.

The roughly sesame seed-size models include functional blood-brain barriers (BBB). In a full-size brain, the BBB would protect the delicate organ from potentially harmful substances that might be circulating through the rest of the body.

"Lack of an authentic human BBB model has been a major hurdle in studying neurological diseases," study co-author Ziyuan Guo, a neurobiologist and stem cell scientist at Cincinnati Children's Hospital Medical Center, said in a statement. "This is an important advance because animal models we currently use in research do not accurately reflect human brain development and BBB functionality."

Guo and his colleagues described their tiny, BBB-carrying brain models in a recent study, published May 15 in the journal Cell Stem Cell.

Related: Lab-grown minibrains will be used as 'biological hardware' to create new biocomputers, scientists propose

In the body, the BBB lines blood vessels that pass through the brain and allows only some substances through, such as hormones and glucose, while blocking out threats, such as toxins and bacteria. It also blocks out many medicines, which poses a challenge for drug developers working on treatments for brain diseases.

The new, lab-grown models combine cerebral organoids 3D clusters of brain cells grown from stem cells with blood-vessel organoids, which are also grown from stem cells but resemble vasculature in the body. Together, these two types of organoids form what the researchers call "assembloids," which simulate how maturing brain and blood vessel cells grow and interact with one another.

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The study showed that, about a month after being combined, the two types of organoids merged together into spherical structures that each measured about the size of a sesame seed. The culture that supports the growth and merger of the two organoids must be carefully controlled, and a physical gel matrix acts as a scaffolding to help support the assembloids, Guo told Live Science in an email.

As proof-of-concept for how these models might be used, the researchers grew assembloids with cells from patients with a cerebral cavernous malformation, meaning a cluster of abnormally shaped blood vessels in their nervous system. These malformations sometimes arise from genetic mutations and can cause symptoms that lead to serious complications, such as stroke and seizure.

The researchers' assembloids captured cellular features seen in people with cerebral cavernous malformations, "offering new insights into the underlying molecular and cellular pathology of cerebral vascular disorders," Guo said in the statement.

In the team's initial tests, the BBB assembloids can be grown for up to five months, or potentially longer, but this hasn't been tested, he added in an email. Four to five months of growth corresponds with roughly the second semester of brain development in the womb.

In the future, the team aims to grow similar assembloids using stem cells from people with different brain diseases, so that the final models would reflect the underlying biology of those conditions.

And more broadly, such assembloids could not only be used to study brain diseases but also to test new drugs, investigate how toxins injure the brain and BBB and reveal novel strategies for delivering medicines through the BBB.

"BBB assembloids represent a game-changing technology with broad implications for neuroscience, drug discovery, and personalized medicine," Guo said in the statement.

Editor's note: This story was updated shortly after publishing with additional quotes from Guo.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun? Send us your questions about how the human body works to community@livescience.com with the subject line "Health Desk Q," and you may see your question answered on the website!

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Past, present, and future of cell replacement therapy for parkinson's disease: a novel emphasis on host immune ... - Nature.com

Stem Cell Res Ther. 2019; 10: 68.

1Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocaw, 50-345 Poland

2Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocaw, 50-425 Poland

1Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocaw, 50-345 Poland

1Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocaw, 50-345 Poland

1Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocaw, 50-345 Poland

2Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocaw, 50-425 Poland

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.

Keywords: Stem cells, Differentiation, Pluripotency, Induced pluripotent stem cell (iPSC), Teratoma formation assay, Stem cell derivation, Growth media, Tissue banks, Tissue transplantation

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 4days, the blastocysts 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 potencymulti-, 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.

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.), 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.

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. 4days 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 cellsoligodendrocytes 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].

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.

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 analysisThis 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 analysisThe unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testingAn 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).

KaryotypeA 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 4872h 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 testingWhen 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.

BacteriologyBacterial 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 arraysThis 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 cytometryThis 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 assaysRecognizing 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 methylationQuality 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.

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.).

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.) [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 12days. 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, NaHCO3, l-ascorbic acid, transferrin, insulin, TGF1, and FGF2 [33]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

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.) [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 frogs 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].

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 patients 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 patients 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].

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 iPSCs 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].

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(TGF); 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 TGF 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.

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 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 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 50years. 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 patients 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 patients own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

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.

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 [8991].

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 zygotes 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.

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.). 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].

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). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Simple and painless for both child and parent

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Stem cells: past, present, and future - PMC - National Center for ...

Orthop Rev (Pavia). 2022; 14(3): 37498.

1Department of Anesthesiology, Mount Sinai Medical Center

1Department of Anesthesiology, Mount Sinai Medical Center

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

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

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

4Department of Emergency Medicine, University of Central Florida

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

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

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

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

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

1Department of Anesthesiology, Mount Sinai Medical Center

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

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

4Department of Emergency Medicine, University of Central Florida

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

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

Corresponding author: Salomon Poliwoda MD; Telephone: 7862716678; email: salomon.pb@gmail.com

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 1950s 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 Parkinsons and Alzheimers 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.

Keywords: Stem cells, regenerative medicine, bone marrow, umbilical cord, placental tissue

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 1950s 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 Parkinsons and Alzheimers 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 patients 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 Whartons 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 (iPSCs) are now being utilized clinically as well. These iPSCs 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

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 (HSCs) 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

HSCs 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 1960s, HSCs 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 1970s and 80s 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.3133 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 HSCs for the near future.

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.3537

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), 2 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.

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.4245 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.4245 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, Crohns disease, multiple sclerosis, fistulas, arthritis, ischemic pathologies, cardiac injury, spinal injury, bone injuries and more.4448

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 Crohns 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 didnt 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

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 cells 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.

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 Parkinsons 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, Whartons 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 Alzheimers and Parkinsons 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.

none

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

Read more here:
Stem cells: a comprehensive review of origins and emerging clinical ...

Kidney Int Suppl (2011). 2011 Sep; 1(3): 6367.

1Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

1Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

2Postgraduation Program in Genetic and Molecular Diagnosis, Universidade Luterana do Brasil, Canoas, Brazil

1Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

2Postgraduation Program in Genetic and Molecular Diagnosis, Universidade Luterana do Brasil, Canoas, Brazil

Stem cells are defined as precursor cells that have the capacity to self-renew and to generate multiple mature cell types. Only after collecting and culturing tissues is it possible to classify cells according to this operational concept. This difficulty in identifying stem cells in situ, without any manipulation, limits the understanding of their true nature. This review aims at presenting, to health professionals interested in this area, an overview on the biology of embryonic and adult stem cells, and their therapeutic potential.

Keywords: adult stem cells, biological characteristics, cell therapy, embryonic stem cells, human diseases

Although the initial concept of stem cells is more than 100 years old,1 and much of its biology and therapeutic potential has been explored in the past three decades, we still know little about their true nature. This review is intended to provide an overview on the biology of stem cells and their therapeutic potential to those interested in this field.

Stem cells are operationally defined as cells that have the potential for unlimited or prolonged self-renewal, as well as the ability to give rise to at least one type of mature, differentiated cells.2, 3 Although this basic definition of stemness' applies generally to stem cells, it is necessary to individually consider embryonic and adult stem cells as they do not share much more than the name and the basic definition above.

In humans, the embryo is defined as the organism from the time of implantation in the uterus until the end of the second month of gestation. Embryonic stem cells (ESCs), however, refer to a much more restricted period, resulting from the isolation and cultivation of cells from the blastocyst, which forms at approximately 5 days after fertilization.4

The zygote, which is the cell resulting from the fertilization of an oocyte by a spermatozoon, is totipotent. Several successive cell divisions generate the morula, with 3264 totipotent cells. After that stage, it develops into the blastocyst, which consists of a hollow ball of cells. Peripheral cells (the trophoblast) of the blastocyst generate the embryonic membranes and placenta, whereas the inner cell mass develops into the fetus. These are the cells that are used to establish stem cell cultures (). They are not totipotent, as they do not have the ability to support the formation of another embryo, and are considered to be pluripotent as they can produce all the cell types of the adult organism. Further development of the embryo leads to the formation of the gastrula, composed of the three germ layers (ectoderm, mesoderm, and endoderm), from which the complete organism develops.

Embryonic stem cell cultivation. The zygote undergoes successive mitotic divisions until a sphere of cellsthe blastocystis formed. In the blastocyst, the trophoblast at its periphery generates the embryonic membranes and placenta, whereas the inner cell mass develops into the fetus. Embryonic stem cells are immortal in culture, having been established from one pluripotent cell collected from the inner cell mass. These are capable of differentiating into any of the mature cell types present in the adult organism.

In 1981, two groups established the first ESC lines from mouse blastocysts, and in 1998 the first human ESC line was generated.5 Although seemingly simple, the procedure is technically demanding because of the need for strictly controlled conditions necessary for the maintenance of the cells in the undifferentiated state. This is particularly important for human ESCs.6 Once established, ESC lines may be maintained in permanent culture, frozen and thawed, and transported between laboratories. It is estimated that there are currently around 250 human ESC lines in the world, widely shared among different groups. The process of establishing an ESC line requires, however, the destruction of the blastocyst, raising ethical issues as scientific investigation alone is not capable of determining whether blastocysts constitute human beings. An alternative method involves the production of ESCs by collection of only one cell from the inner cell mass, allowing implantation of the remaining cells in the womb. However, ethical considerations still remain as it has to be tested whether the remaining cells can develop into a normal human being.

Cultured ESCs show defined characteristics: they are pluripotent, capable of differentiating into cells derived from all three germ layers; they are immortal in culture and may be maintained for several hundred passages in the undifferentiated state; and they maintain a normal chromosomal composition.

Molecular characterization of ESCs is well developed, and they are known to express surface markers such as CD9, CD24, and alkaline phosphatase, and several genes involved with pluripotency, including Oct-4, Rex-1, SOX-2, Nanog, LIN28, Thy-1, and SSEA-3 and -4.7 Expression of high levels of telomerase explains their immortality in culture.

ESC research focuses mainly on two issues, both of which have shown significant progress in the past few years.6 The first point explores how to better maintain the cells in long-term culture, without significant modifications of their genetic composition and, in the case of human ESCs, avoiding the need for animal products in the culture. Generally, the cells are maintained in culture on feeder cells such as mouse fibroblasts. The second point focuses on how to differentiate the cells into the many mature cell types that are necessary for the potential treatment of different diseases. ESCs can be induced to differentiate into various cell types in suspension culture, resulting in three-dimensional cell aggregates called embryoid bodies. This tendency of ESCs to differentiate spontaneously may not always be desirable. A technical challenge is to control the differentiation process: although the addition of growth factors directs the differentiation process, usually the cultures spontaneously differentiate into various cell types. It is thus necessary to use methods that allow removal of undifferentiated ESCs from cultures in which the differentiated cell types are the desired product.

Recently, methods for direct reprogramming of adult cells to induced pluripotent stem cells have been developed.8 In the process, mature cells from the patient are treated in vitro with genes that dedifferentiate' them to a pluripotent stage, similar to an ESC (). Induced pluripotent stem cells are believed to be identical to natural pluripotent ESCs in many respects, including the expression of specific genes and proteins, chromatin methylation patterns, culture kinetics, in vitro differentiation patterns, and teratoma formation. Besides avoiding the ethical issues associated with the destruction of human embryos, this approach allows the generation of patient-specific cells of any lineage. Problems related to the genetic modification of target cells, however, must still be resolved before induced pluripotent stem cells may be clinically tested.

Production of induced pluripotent stem (iPS) cells. iPS cells are produced by treating mature cells, such as fibroblasts, with genes that dedifferentiate' them to a pluripotent stage, similar to an embryonic stem cell. Viral vectors, such as retroviruses, are generally used for gene transfer. The transformed cells become morphologically and biochemically similar to pluripotent stem cells, with the advantage of representing autologous cells in therapeutic applications.

The principal advantage of ESCs over adult stem cells is related to their pluripotency and limitless expansion in culture, as they have the potential to give rise to all cell types composing the adult organism. This potential is exploited in vitro to develop specialized cells that are then used in therapy.

Owing mainly to safety issues, the clinical use of hESCs is much more restricted than that of adult stem cells. As proof of pluripotency, ESC lineages injected into immunodeficient mice must lead to teratoma formation, with derivatives of all three germ layers. Only differentiated cells derived from ESCs may be administered to patients, as any contaminating undifferentiated cells could give rise to cancer. The first clinical trial using human ESC-derived cells, which in this case are oligodendrocyte progenitor cells, was started in October 2010. Care must be taken, however, to not call this procedure human ESC therapy', as the cells to be used are no longer ESCs.

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Biology of stem cells: an overview - PMC - National Center for ...

Stem cells are special human cells that can develop into many different types of cells, from muscle cells to brain cells.

Stem cells also have the ability to repair damaged cells. These cells have strong healing power. They can evolve into any type of cell.

Research on stem cells is going on, and it is believed that stem cell therapies can cure ailments like paralysis and Alzheimers as well. Let us have a detailed look at stem cells, their types and their functions.

Also Read: Gene Therapy

Stem cells are of the following different types:

The fertilized egg begins to divide immediately. All the cells in the young embryo are totipotent cells. These cells form a hollow structure within a few days. Cells in one region group together to form the inner cell mass. This contains pluripotent cells that make up the developing foetus.

The embryonic stem cells can be further classified as:

These stem cells are obtained from developed organs and tissues. They can repair and replace the damaged tissues in the region where they are located. For eg., hematopoietic stem cells are found in the bone marrow. These stem cells are used in bone marrow transplants to treat specific types of cancers.

These cells have been tested and arranged by converting tissue-specific cells into embryonic cells in the lab. These cells are accepted as an important tool to learn about the normal development, onset and progression of the disease and are also helpful in testing various drugs. These stem cells share the same characteristics as embryonic cells do. They also have the potential to give rise to all the different types of cells in the human body.

These cells are mainly formed from the connective tissues surrounding other tissues and organs, known as the stroma. These mesenchymal stem cells are accurately called stromal cells. The first mesenchymal stem cells were found in the bone marrow that is capable of developing bones, fat cells, and cartilage.

There are different mesenchymal stem cells that are used to treat various diseases as they have been developed from different tissues of the human body. The characteristics of mesenchymal stem cells depend on the organ from where they originate.

Following are the important applications of stem cells:

This is the most important application of stem cells. The stem cells can be used to grow a specific type of tissue or organ. This can be helpful in kidney and liver transplants. The doctors have already used the stem cells from beneath the epidermis to develop skin tissue that can repair severe burns or other injuries by tissue grafting.

A team of researchers have developed blood vessels in mice using human stem cells. Within two weeks of implantation, the blood vessels formed their network and were as efficient as the natural vessels.

Stem cells can also treat diseases such as Parkinsons disease and Alzheimers. These can help to replenish the damaged brain cells. Researchers have tried to differentiate embryonic stem cells into these types of cells and make it possible to treat diseases.

The adult hematopoietic stem cells are used to treat cancers, sickle cell anaemia, and other immunodeficiency diseases. These stem cells can be used to produce red blood cells and white blood cells in the body.

Stem Cells originate from different parts of the body. Adult stem cells can be found in specific tissues in the human body. Matured cells are specialized to conduct various functions. Generally, these cells can develop the kind of cells found in tissues where they reside.

Embryonic Stem Cells are derived from 5-day-old blastocysts that develop into embryos and are pluripotent in nature. These cells can develop any type of cell and tissue in the body. These cells have the potential to regenerate all the cells and tissues that have been lost because of any kind of injury or disease.

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Stem-cell therapy is the use of stem cells to cure or prevent a disease or condition. The damaged cells are repaired by the generated stem cells, which can also hasten the healing process in the injured tissue. These cells are essential for the regeneration and transplanting of tissue.

Stem cells have the capacity to self-renew and differentiate into specialized cell types. Totipotent stem cells come from an early embryo and can differentiate into all possible types of stem cells.

The four types of stem cells are the embryonic stem cells, adult stem cells, induced pluripotent stem cells and mesenchymal stem cells

Adult stem cells are undifferentiated cells taken from tissues and developing organs. They can replace and restore damaged tissues. Example hematopoietic stem cells in the bone marrow.

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Definition

A stem cell, found in embryos (embryonic stem cell) and adults (somatic stem cell), is an immature, non-specialized cell that can differentiate into one or more specific functioning or regenerating cell types. This makes them of use in the treatment of degenerating diseases. A totipotent stem cell can become any cell type within the organism in which it is found; a pluripotent cell can become any of a wide range of cell types; a unipotent cell is restricted to one cell type.

A stem cell is an early form of cell that has the power to become a specialized cell. The first totipotent stem cell in mammals is the zygote formed after the sperm has fertilized the egg. Every cell in the body is produced from this one cell.

While some textbooks say that cancer cells can be totipotent, this is not the case. A totipotent cell must be capable of developing into a complete organism and its supporting tissues through division. Some cancer cells can differentiate into other tissues, but they are not totipotent. Once a stem cell (SC) differentiates into a cell that is unable to become every cell type both in the organism and in the mother (as a placenta-forming cell), it is no longer totipotent but pluripotent.

SCs can be totipotent (the zygote and the zygotes first stages of division into blastomeres), pluripotent, multipotent, oligopotent, or unipotent. It does not have any function except to produce cell forms that differ from its own structure. Its sole role is to differentiate. How many cell types a stem cell can differentiate into is decided according to its potency level. The controlling mechanism of where and when this cell divides to become another cell type is found in the DNA.

Stem cell types are categorized according to potency level. The higher the stem cell potency level, the higher the range of differentiation. Somatic (adult) SCs are found in all adult and fetal tissues; they replace damaged cells within that tissue and are not totipotent.

The totipotent embryonic stem cell can differentiate into all cell types and also form placental tissue inside the mother. The first eight cells of a single fertilized egg (zygote) are totipotent. After the first round of cell division, the zygote becomes two identical blastomeres; in the second round, the two blastomeres become four blastomeres; in the third cycle of division, eight blastomeres are produced. Only up to this point is the SC totipotent. Should a single blastomere become separated from the group at this very early stage, identical twins are the result. If two blastomeres separate from the main group, identical triplets can develop.

As each totipotent cell division called cleavage at this early stage takes between twelve to twenty-four hours, totipotent embryonic stem cells can only be extracted between one and a half and three days after fertilization.

A pluripotent stem cell can differentiate into any adult cell type but not into placental tissue. Once eight blastomeres have formed, the first round of differentiation occurs to form an outer trophoblast and inner embryoblast. If an entire group of early differentiated pluripotent cells become separated at this point, it is unlikely an embryo will develop. The trophoblast layer becomes the placenta and the embryoblast the embryo.

Embryoblast cells differentiate into any of the cells of the ectoderm, mesoderm, and endoderm of an embryo.

Most of the SCs used in research today are pluripotent embryonic cells. Ethical issues exist as, for large groups of the population, life begins at conception.

Induced pluripotent stem cells (iPSCs) are produced in the laboratory. These are somatic cells engineered to behave like embryonic ones. At present, their use is limited to research but they do mean fewer ethical issues. An adult can opt to donate his or her stem cells to international banks that may or may not match recipients from all over the globe.

A multipotent stem cell is an adult cell. This does not mean it is only found in adults a fetus of approximately ten weeks is composed of multipotent adult SCs. Division produces one specialized daughter cell and one undifferentiated (stem) daughter cell. Examples of multipotent cells are:

It is possible to extract SCs from the umbilical cord during birth. Cord blood stem cells produce blood and mesenchymal cells. As umbilical stem cells have a higher level of potency than other multipotent SCs with fewer specific features, they produce a lower immune response when inserted into another organism of the same species.

The oligopotent stem cell only differentiates into a small group of related cell types. Lymphoid and myeloid stem cells, and corneal squamous epithelium SCs continuously renew the short-lived cells of their specific tissues.

The unipotent SC produces a single cell type to regenerate populations. Nearly all of the bodys cells are unipotent; the difference between a normal cell and a stem cell is this renewing ability. Unipotent progenitor cells allow the regeneration of cells with a short lifespan; examples of unipotent progenitors are muscle stem cells and epidermal stem cells.

When an SC is damaged and cannot differentiate, or when a differentiated stem cell does not divide (as with red blood cells), it becomes a nullipotent stem cell.

A good example is the process of skin burn repair. When skin is sunburned, the top (dead) layers of skin are damaged; new cells produced by unipotent basal skin stem cells eventually replace them. When a burn is deep and the basal cells are damaged, they can no longer divide or differentiate; they have been damaged to the extent that they are nullipotent.

Instead, the SCs of the underlying connective tissue differentiate and form a scar that is not skin. Skin grafts from healthy tissue placed onto a deep burn reduce scarring because they introduce undamaged basal SCs to unhealthy tissue.

Stem cell structure depends on the potency level. A totipotent cell has the structure of a zygote or a blastomere. A unipotent cell will more closely resemble the cell it differentiates into.

Most SCs are round with prominent nucleoli and a high nucleus to cytoplasm ratio (a large nucleus). They contain the same organelles as other cells rough and smooth endoplasmic reticulum, Golgi apparatus, mitochondria, lysosomes, centrosomes, and centrioles.

In laboratories, embryonic SCs reproduce for indefinite periods and are referred to as immortal cells. The word immortal has led many people to believe that these treatments can halt the aging process. This is not at least not yet true.

Propagated cells can theoretically be engineered to differentiate in vivo (in a living organism) or in vitro (outside a living organism) to form any of the two hundred and twenty adult human cell types.

Cells produced in the laboratory are much less likely to be rejected by the bodies of non-related subjects. Stem cell treatment, therefore, is considered to be the future of organ transplant and tissue renewal therapies.

Stem cell research does not only concern the replacement or repair of damaged or aging tissue. It also includes looking into the signals that influence differentiation. External or environmental factors, cell signaling, and genetic control of stem cell specialization processes help us to understand how the body heals itself and regulates tissue renewal.

Even so, stem cell technologies are still in very early stages. We must first understand the exact processes that turn a totipotent cell into a liver cell, for example, before a stem cell therapy can be developed for liver damage. If this process is not exactly understood, any one of thousands of variables could cause SC injections to differentiate into undesired tissue types. Even the nutritional gel of a laboratory culture could affect which daughter cells are produced.

Low immunity in combination with human embryonic SC transplant has been known to lead to teratoma formation. One study showed how the human stem cell injected into immune-compromised mice caused human tissue teratoma growth. Naturally-formed teratomas first gave scientists the idea of the existence of pluripotent cells in the 1950s.

Stem cell therapy is still undergoing clinical trials in a small selection of diseases, not always with the best results. The treatment of blindness caused by macular degeneration with stem cell injection seems to help some visually-impaired patients but certainly not all. Ones own SCs are increasingly being used to grow tissue that, once large enough, can be transplanted without rejection risk. Tracheal transplants, for example, have been performed using SC-generated implants.

In 2020, the Food and Drug Administration reported: Currently, the only stem cell products that are FDA-approved for use in the United States consist of blood-forming stem cells.

Since then, this list has grown as more clinical research achieves results. Approved treatments now include:

Unfortunately, many clinics offer approved stem cell treatments that are yet to be either proven or approved. Certainly, our lack of knowledge regarding when, how, and into what an SC differentiates should make us wait until more clinical studies and research have been performed.

Stem cell hair transplants are offered all over the world and often advertised as FDA-approved therapies this is very far from the case. The risk of teratoma and even neoplasm (benign or malignant tumor) development when internal or external environments change the course of SC differentiation is a possibility that should not be ignored.

We still have decades of research before SC therapy gets anywhere near the initial, hopeful reports that filled newspapers at the beginning of this century. While studies must deal with a huge number of variables, it is expected that stem cell therapy will become a future first-line treatment for degenerative and immune disorders.

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Stem Cell - The Definitive Guide | Biology Dictionary

'I couldn't just give up on my dad' | Round Rock son donates stem cells to father battling leukemia  KVUE.com

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'I couldn't just give up on my dad' | Round Rock son donates stem cells to father battling leukemia - KVUE.com

What is a stem cell? What is a stem cell?

An illustration showing a stem cell giving rise to more stem cells or specialised cells. Image credit: Genome Research Limited

An illustration showing different types of stem cell in the body. Image credit: Genome Research Limited

A scientist here at the Wellcome Genome Campus working on induced pluripotant stem cells. Image credit: Genome Research Limited

These heart cells were grown from stem cells in a petri dish and can be used to study the beating rhythm of the heart. Image credit: The McEwen Centre for Regenerative Medicine, University Health Network

An illustration showing how stem cells can be used to produce retinal pigment epithelium (RPE) cells that can be used to treat patients with age-related macular degeneration (AMD). Image credit: Genome Research Limited

This page was last updated on 2021-07-21

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