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Induced stem cells   


Induced stem cells   (iSC) are   stem cells   artificially derived from some other ( somatic ,   reproductive ,   pluripotent   etc.) cell types by induced (i.e., initiated, forced)   epigenetic   reprogramming. In accordance to the   developmental potentiality and the degree of cell dedifferentiation   caused by induced reprogramming they are distinguished and subdivided as: induced   totipotent ,   induced pluripotent stem cells (iPSc)   and, obtained by so-called   direct reprogramming   or directed forced   differentiation , induced   progenitor   (multipotent or unipotent ) stem cells, also called induced   somatic stem cells . Currently, there are three ways to reprogram somatic cells into stem cells [1].  These are:

1.       Transplantation of nuclei   taken from somatic cells into a fertilized egg or oocyt from which the nucleus is removed prior [2] [3] [4] [5]

2.       Fusion   of somatic cells with pluripotent stem cells [6]   and

3.       Modification of somatic cells, inducing its transformation into a stem cell, using: the genetic material encoding   reprogramming protein factors , [7] [8] [9]   recombinant proteins; [10]   microRNA, [11] [12] [13] [14] [15]   a synthetic, self-replicating polycistronic RNA [16] and low-molecular weight biologically active substances. [17] [18] [19] [20] [21]


 1   Metaplasia and Transdetermination - natural processes of induction

·2   Induced totipotent cells and their use for cloning and generation of genetically modified animals

3   iPSc as a result of radical rejuvenation

      3.1   Chemically induced pluripotent cells (CiPSCs)

      3.2   Method for producing cells induced to differentiate from iPSCs in the teratoma under in vivo conditions

      3.3   Cell therapy with retina cells obtained from iPSCs

      3.4   Generation of lung and airway epithelial cells from iPSC

      3.5   Differentiation of iPSCs into reproductive cells

4   Induced progenitor stem cells

      4.1   Methods of direct transdifferentiation

      4.1.1   Forced transdifferentiation of mature cells by a single transcription factor

      4.2   Reprogramming by means of a phased process modeling regeneration

      4.3   Transdifferentiation by using an antibody

      4.4   Conditionally reprogrammed cells (CRCs)

      4.5   Indirect lineage conversion (ILC)

      4.6   Reprogramming induced by the influence on the outer membrane glycoprotein

      4.7   Stimulus-triggered acquisition of pluripotency (STAP) cells

      4.8   Reprogramming through a physical approach

      4.9   Induced neural stem cells (iNSCs)

      4.10   Oligodendrocyte precursor cells (OPCs)

      4.11   Induced cardiomyocytes (iCMs)

      4.12   Direct Reprogramming of Adult Cells to Nephron Progenitors (iNP)

      4.13   Bioengineering of the cells of blood vessels

      4.14   Bioengineering of blood stem cells

      4.14.1   Red blood cells (RBC)

      4.14.2   Platelets

      4.14.3   Immune cells

      4.15   Induced Mesenchymal stem cells (iMSCs)

      4.15.1   Induction of human iPSc to Generate Mesenchymal Stem/Stromal Cells

      4.15.2   Dedifferentiated adipocytes: an alternative source of MSC

      4.16   Induced chondrogenic cells (iChon cells)

5   Sources of cells for reprogramming

6   See also

7   Notes

      7.1   References for further reading

8   References


Metaplasia and Transdetermination - natural processes of induction

The reversible transformation of one differentiated cell type to another type of mature differentiated cells is called   metaplasia . [22]   This transition from one cell type to another can be a part of the normal maturation process, or caused by some of its inducing stimulus. For example: transformation of cells of the iris to the lens in the process of maturation and transformation of the retinal pigment epithelium cells into the neural retina during regeneration in adult newt eyes. This process allows the body to replace the original cells not suitable to new conditions, into new cells that are more suited to new conditions. In experiments on cells in Drosophila imaginal discs, it was found that there are a limited number of standard discrete states of differentiation and the cells have to choose one of them. The fact that transdetermination (change of the path of differentiation) often take place not in one, but in a group of cells shows that it is not caused by a mutation but is induced. [23] [24]

Some types of mature, specialized adult cells can naturally revert to stem cells. For example, differentiated cells, which are called chief cells and express the stem cell marker Troy, normally produce digestive fluids for the stomach, yet they can change back into stem cells to make temporary repairs in significant stomach injuries, such as a cut or damage from infection. Moreover, they are making this transition even in the absence of noticeable injuries and are capable of replenishing entire gastric units, in essence serving as quiescent “reserve” stem cells. [25]   Differentiated airway epithelial cells can revert into stable and functional stem cells in vivo. [26]   After injury, mature terminally differentiated kidney cells dedifferentiate into more primordial versions of themselves, and then differentiate into the cell types needing replacement in the damaged tissue [27]   Macrophages can self-renew by local proliferation of mature differentiated cells. [28]   In   Newts , muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget what type of cell they have been. This capacity to regenerate tissue does not decline with age, which may be linked to their ability to make new stem cells from muscle cells on demand. [29]

There are also a variety of nontumorigenic stem cells with the ability to generate the multiple cell types. For instance, multilineage-differentiating stress-enduring   (Muse)   cells are the stress-tolerant adult human stem cells that can self-renew; form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency; and can differentiate into endodermal, ectodermal, and mesodermal cells both in vitro and in vivo. [30] [31] [32] [33] [34]

Detailed description of some other well-documented examples of   transdifferentiation , and their significance in development and regeneration are reviewed in. [35]

Induced totipotent cells and their use for cloning and generation of genetically modified animals

Induced totipotent cells usually can be obtained by reprogramming somatic cells by   somatic-cell nuclear transfer   (SCNT) to the recipient eggs or oocytes. [3] [5] [36] [37] [38]   Sometimes may be used the oocytes of other species, such as sheep. [39] [40]   New possibilities for creating genetically modified animals opens method of induced androgenetic haploid embryonic stem cells, which can be used instead of sperm. These cells, synchronized in M phase and injected into the oocyte allow to get viable offspring. [41] These developments, together with data on the possibility to obtain unlimited number of oocytes from mitotically active reproductive stem cells [42]   offer the possibility of industrial production of transgenic farm animals. Repeated recloning of viable mice through a somatic cell nuclear transfer method that includes a histone deacetylase inhibitor – trichostatin, added to the cell culture medium, [43]   show that it may be possible to reclone animals indefinitely without any visible accumulation of reprogramming or genomic errors   [44]   However, research into technologies to develop sperm and egg cells from stem cells bring up bioethical issues.

Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes. [45] [46] [47] For example, the technology have been developed that could prevent inherited mitochondrial disease being passed on to the next generation. Mitochondria, often described as the powerhouse of the cell, contain genetic material, which is passed from mother to child. Mutations on mitochondrial DNA can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and several other neurological diseases. The nucleus from one human egg cell have been transferred to another egg, in effect swapping the cell cytoplasm, which includes the mitochondria (and their DNA), creating a cell that could be regarded as having two mothers. The eggs were then fertilised, and the resulting embryonic stem cells carried the swapped mitochondrial DNA. [48]

In the case of late-generation telomerase-deficient (Terc−/−) mice, SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming. [49]

Read more about the latest achievements of the cloning techniques and the generation of totipotent cells, in: [50]

iPSc as a result of radical rejuvenation

First iPSc were obtained in the form of transplantable   teratocarcinoma   induced by the graft taken from mouse embryos. [51]   It was shown that teratocarcinoma formed from somatic cells. [52]   The fact that normal genetically mosaic mice can be obtained from malignant teratocarcinoma cells confirmed their pluripotency. [53] [54] [55]   It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent embryonic stem cells in an undifferentiated state, by supplying the culture medium with various factors. [56]   Thus, as early as in the 1980s, it became clear that the transplantation of pluripotent or embryonic stem cells into the body of adult mammals, usually leads to the formation of   teratomas , which can then turn into a malignant tumor teratocarcinoma. [57]   If, however, to put the teratocarcinoma cells into the early mammal embryo (at the blastocyst stage), they became incorporated in the cell mass of blastocysts and from such a chimeric (i.e. composed of cells from different organisms) blastocyst often develops normal chimeric animal. [58] [59] [60]   This indicated that the cause of the teratoma is a dissonance - mutual misunderstanding of "speech" of young donor cells and surrounding adult cells (so-called   niche ) of the recipient.

In August 2006, Japanese researchers circumvented the need for an oocyte, which is required for SCNT-mediated nuclear reprogramming method. By reprograming mouse embryonic fibroblasts into pluripotent stem cell via the ectopic expression of only four transcription factors, namely Oct4, Sox2, Klf4, and c-Myc, they proved that the overexpression of a small number of factors can sometimes push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes. [7] Obviously, mechanisms of reprogramming are linked, rather than independent, and are centered on a small number of genes. [61]   The properties of IPSC were very similar to embryonic stem cells (ESCs). iPSCs have been shown to support the development of all-iPSC mice using tetraploid (4n) embryo, [62] [63]   the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to give rise to all-iPSC mice on the score of aberrant epigenetic silencing of the imprinted   Dlk1-Dio3 gene   cluster. [19]   An important advantage of iPSC to ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adults and even elderly patients [9]   Reprogramming of somatic cells to iPSC leads to rejuvenation. It was found that reprogramming to iPSC leads to telomere lengthening and shortening after their subsequent differentiation back into fibroblast-like derivatives. [64]   Thus, reprogramming of somatic cells to iPSC leads to the restoration of embryonic telomere length, [65] and hence increases the potential number of cell divisions limited by   Hayflick limit . [66] [67]   Therefore, technology of iPSC should be seen as a radical way to rejuvenation. However, because of the dissonance between rejuvenated cells and their surrounding (so-called niche   ) of older cells of the recipient, the injection of the patient by his own iPSC usually leads to an immune response, [68]   which can be used for medical purposes, [69]   or the formation of tumors such as teratoma. [70]   The reason for this probably lies in the fact that some cells differentiated from ESC and iPSC in vivo continue to synthesize the embryonic isoforms of protein. [71]   So, the immune system might detect and attack cells that are not cooperating properly.

Hope gives us study that showed that a small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering apoptosis   (via   cytochrome c   release across the   mitochondrial   outer membrane in human pluripotent stem cells but not in differentiated cells), while shortly after differentiation their daughter cells became resistant to death. When MitoBloCK-6 introduced to differentiated cell lines, the cells remained healthy. The key to the survival of the differentiated cells, when the cells are exposed to MitoBloCK-6, may be due to the changes undergone by pluripotent stem cell mitochondria in the process of cell differentiation. This ability of MitoBloCK-6 to separate the pluripotent and differentiated cell lines have potential to reduce the risk of teratomas and other problems in regenerative medicine treatment strategies. [72]   Recently been identified others small molecules (selective cytotoxic inhibitors of hPSCs) that prevented human pluripotent stem cells from forming teratomas in mice following transplantation. The most potent and selective compound of them (PluriSIn #1) inhibits stearoyl-coA desaturase (the key enzyme in oleic acid biosynthesis), which finally results in apoptosis. With the help of this molecule the undifferentiated cells can be selectively removed from culture. [73] [74]   An efficient strategy to selectively eliminate pluripotent cells with teratoma potential is targeting pluripotent stem cell-specific antiapoptotic factor(s)   (i.e.,   survivin   or Bcl10). Indeed, a single treatment of mixed population with chemical inhibitors of survivin (e.g., quercetin   or YM155) can induce selective and complete cell death of undifferentiated hPSCs and, according to authors, is sufficient to prevent teratoma formation after transplantation of iPSC-derived cells. [75]   However, it is unlikely that any kind of preliminary clearance, even the most sophisticated pre-treatment, [76]   is able to secure the replanting iPSC or ESC, as after the selective removal of pluripotent cells, they re-emerge quickly by converting differentiated cells back into stem cells, which leads to the formation of tumors, [77] [78] [79]   This may be due to the disorder of   let-7   regulation of its target Nr6a1 (also known as   Germ cell nuclear factor   - GCNF), an embryonic transcriptional repressor of pluripotency genes that regulates gene expression in adult fibroblasts following miRNA loss. [80] [81]

Teratoma formation by pluripotent stem cells may be caused by low activity of   PTEN enzyme , reported to promote the survival of a small population (0,1-5% of total population) of highly tumorigenic, aggressive, teratoma-initiating embryonic-like carcinoma cells during differentiation. The survival of these teratoma-initiating cells is associated with failed repression of   Nanog   as well as a propensity for increased glucose and cholesterol metabolism. [82]   These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells. [83]   In connection with the above safety problems, the use iPSC for cell therapy is still limited. [84] [85]   However, they can be used for a variety of other purposes - including the modeling of disease, [86] [87]   screening (selective selection) of drugs, toxicity testing of various drugs. [88] [89]

It is interesting to note that the tissue grown from iPSCs, placed in the "chimeric" embryos in the early stages of mouse development, practically do not cause an immune response (after the embryos have grown into adult mice) and are suitable for   autologous transplantation [90] [91] [92]   At the same time, full reprogramming of adult cells in vivo within tissues by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs. [93] [94]

Chemically induced pluripotent cells (CiPSCs)

By using solely small molecules, Deng Hongkui and colleagues demonstrated that endogenous “master genes” are enough for cell fate reprogramming. They induced a pluripotent state in adult cells from mice using seven small-molecule compounds. [17]   The effectiveness of the method is quite high: it was able to convert 0.2% of the adult tissue cells into iPSCs, which is comparable to the gene insertion conversion rate. The authors note that the mice generated from CiPSCs were "100% viable and apparently healthy for up to 6 months”.So. This chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications. [95] [96]

Method for producing cells induced to differentiate from iPSCs in the teratoma under in vivo conditions

The fact that human iPSCs capable of forming teratomas not only in humans but also in some animal body, in particular in mice or pigs, allowed to develop a method for differentiation of iPSCs in vivo. For this purpose, iPSCs with an agent for inducing differentiation into target cells are injected to   genetically modified   pig or mouse that has suppressed immune system activation on human cells. The formed after a while teratoma is cut out and used for the isolation of the necessary differentiated human cells [97]   by means of monoclonal antibody   to tissue-specific markers on the surface of these cells. This method has been successfully used for the production of functional myeloid, erythroid, and lymphoid human cells suitable for transplantation (yet only to mice). [98]   Mice engrafted with human iPSC teratoma-derived hematopoietic cells produced human B and T cells capable of functional immune responses. These results offer hope that in vivo generation of patient customized cells is feasible, providing materials that could be useful for transplantation, human antibody generation, and drug screening applications. Using MitoBloCK-6   [72]   and / or PluriSIn # 1 the differentiated progenitor cells can be further purified from teratoma forming pluripotent cells. The fact, that the differentiation takes place in a teratoma, offers hope that the resulting cells are sufficiently stable to stimuli able to cause their transition back to the dedifferentiated (pluripotent) state, and therefore safe. A similar in vivo differentiation system, yielding engraftable hematopoietic stem cells from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis, was described by Suzuki et al. [99]   They noted that neither leukemia nor tumors were observed in recipients after intravenous injection of iPSC-derived hematopoietic stem cells into irradiated recipients. Moreover, this injection resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Such system provides a useful tool for practical application of iPSCs in the treatment of hematologic and immunologic diseases. [100]

For further development of this method animal in which is grown the human cell graft, for example mouse, must have so modified genome that all its cells express and have on its surface human   SIRP α . [101]   To prevent rejection after transplantation to the patient of the allogenic organ or tissue, grown from the pluripotent stem cells in vivo in the animal, these cells should express two molecules: CTLA4-Ig , which disrupts T cell costimulatory pathways, and   PD-L1 , which activates T cell inhibitory pathway. [102]

See also: Robert Lanza, Michael West (2013)   Method for facilitating the production of differentiated cell types and tissues from embryonic and adult pluripotent and multipotent cells . Patent US 20130058900 A1

Cell therapy with retina cells obtained from iPSCs

In the near-future, clinical trials designed to demonstrate the safety of the use of iPSCs for cell therapy of the people with age-related macular degeneration, a disease causing blindness through retina damaging, will begin. There are several articles describing methods for producing retinal cells from iPSCs [103]   [104]   and how to use them for cell therapy. [105] [106]   Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced visual-guided behaviors of experimental animals for 6 weeks after transplantation. [107]   However, clinical trials have been successful: ten patients suffering from retinitis pigmentosa have had their eyesight restored—including a woman who had only 17 percent of her vision left.   [108]

Generation of lung and airway epithelial cells from iPSC

Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or   chronic obstructive pulmonary disease   and   asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal, and financial burden. So there is an urgent need for effective cell therapy and   lung   tissue engineering . [109] [110]   Several protocols have been developed for generation of the most cell types of the   respiratory system , which may be useful for deriving patient-specific therapeutic cells. [111] [112] [113] [114] [115]

Differentiation of iPSCs into reproductive cells

Some lines of iPSCs have the potentiality to differentiate into male germ cells and oocyte-like cells in an appropriate niche (by culturing in retinoic acid and porcine follicular fluid differentiation medium or seminiferous tubule transplantation). Moreover, iPSC transplantation make a contribution to repairing the testis of infertile mice, demonstrating the potentiality of gamete derivation from iPSCs in vivo and in vitro. [116] [117] [118]

Induced progenitor stem cells

Methods of direct transdifferentiation

Due to the fact that the use of iPSC for cell therapy is associated with significant risk of cancer and tumors there is urgent need to develop methods for safer cell lines suitable for use in the clinic. An alternative to the methods of iPSC technique is the so-called "direct reprogramming" - induced by certain factors direct transdifferentiation of cells without passing through the stages of the pluripotent state. [119] [120] [121] [122] [123] [124]   The basis for this approach laid the study of Taylor and Jones, who showed that 5-azacytidine - reagent causing demethylation of DNA - can cause the formation of myogenic, chondrogenic, and adipogenic clones in the immortal cell line of mouse embryonic fibroblasts [125]   and Weintraub et al., who found that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming, [126] [127] [128]   Compared with iPSC whose reprogramming need at least two weeks, the formation of induced progenitor cells occurs relatively quickly - sometimes within a few days and the efficiency of reprogramming are usually many times higher. This reprogramming does not always require cell division. [129]   But the main thing is that the resulting from such reprogramming multipotent somatic stem cells are more suitable for cell therapy because they do not form teratomas. [124]

Forced transdifferentiation of mature cells by a single transcription factor

It was thought that only early embryonic cells could be coaxed into changing their identity. Mature cells are very resistant to changing their identity once they've committed to a specific kind. However, it has been found that brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, highly specialized non-endodermal cells of the pharynx into fully differentiated intestinal cells in intact larvae and adult roundworm Caenorhabditis elegans. And there was no apparent requirement for a dedifferentiated intermediate during this transdifferentiation process. [130]

Reprogramming by means of a phased process modeling regeneration

Another way of reprogramming is the simulation of the processes that occur during amphibian limb regeneration. In urodele amphibians, an early step in limb regeneration is skeletal muscle fiber dedifferentiation into a cellulate that proliferates to contribute new limb tissue, whereas mammalian muscle cannot dedifferentiate after injury. However, sequential small molecule treatment of the muscle fiber with myoseverin, reversine (the aurora B kinase inhibitor) and some other chemicals: BIO (glycogen synthase-3 kinase inhibitor), lysophosphatidic acid (pleiotropic activator of G-protein-coupled receptors), SB203580 (p38 MAP kinase inhibitor), or SQ22536 (adenylyl cyclase inhibitor) causes the formation of new muscle cell types as well as other cell types such as precursors to fat, bone, and nervous system cells. [131] [132]

Transdifferentiation by using an antibody

The researchers discovered   GCSF -mimicking   antibody   that can activate a growth-stimulating receptor on marrow cells in a way that induces marrow stem cells—which normally develop into white blood cells—to become neural progenitor cells. The new technique, [133]   that enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect, has been used for such purpose [134] [135]

Conditionally reprogrammed cells (CRCs)

Schlegel   and Liu   [136]   demonstrated that the combination of feeder cells   [137]   (a review is given in [138]   and [139] ) and a Rho kinase inhibitor (Y-27632)   [140] [141]   induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro and this process occurs without the need for transduction of exogenous viral or cellular genes. These cells has been termed as "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population rather than the selection of a minor subpopulation. CRCs do not express high levels of proteins characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2, Oct4, Nanog, or Klf4). This induction of CRCs is reversible, and removal of Y-27632 and feeders allows the cells to differentiate normally. [136] [142] [143]   CRC technology can generate 2×10 6   cells in 5 to 6 days from needle biopsies, and can generate cultures from cryopreserved tissue and from fewer than four viable cells. CRCs retain a normal karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors. [136] [144] [145]   The ability to rapidly generate many tumor cells from small biopsy specimens and frozen tissue provides significant opportunities for cell-based diagnostics and therapeutics (including chemosensitivity testing) and greatly expands the value of biobanking. [136] [144] [145]   Using conditionally reprogrammed cells technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor. [146]   In addition, the CRC method allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host. While their initial studies revealed that co-culturing of epithelial cells with Swiss 3T3 cells J2 was essential for the induction of CRCs,   Schlegel   and Liu   [147]   have now shown with transwell culture plates that physical contact between feeders and epithelial cells is not required for inducing CRCs and, more important, that irradiation of the feeder cells is required for this induction. Consistent with the transwell experiments, conditioned medium is shown to induce and maintain CRCs, which is accompanied by a concomitant increase of cellular telomerase activity. The activity of the conditioned medium correlated directly with radiation-induced apoptosis of the feeder cells. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells. [147]

A different approach to obtain conditionally reprogrammed cells is to inhibit   CD47   - a   membrane protein   that is the   thrombospondin-1 receptor. It was shown that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent   embryoid body -like clusters. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells in vitro and in vivo. It is obvious that thrombospondin-1 is a key environmental signal that inhibits stem cell self-renewal via CD47. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors. [148]   Interesting to note that in vivo blockade of CD47 using an antisense   morpholino   increases survival of mice exposed to lethal total body irradiation due to increased proliferative capacity of bone marrow derived cells and radioprotection of radiosensitive gastrointestinal tissues. [149]

Indirect lineage conversion (ILC)

A reprogramming methodology developed in which somatic cells transition through a plastic intermediate state of partially reprogrammed cells (pre-iPSC), induced by brief exposure to reprogramming factors, followed by differentiation by specially developed chemical environment (artificial niche). [150]   It is assumed that this new method could be both more efficient and safer, since it does not seem to produce tumors or other undesirable genetic changes, and results in much greater yield than other methods. However, the safety of these cells all the same questionable - considering that lineage conversion from pre-iPSC relies on the use of iPSC reprogramming conditions, it can not be excluded that a fraction of the cells could acquire pluripotent properties if they do not stop the de-differentation process in vitro or due to further de-differentiation in vivo.

Reprogramming induced by the influence on the outer membrane glycoprotein

A common feature of pluripotent stem cells, taken from different sources, is the specific nature of protein   glycosylation   of their outer membrane. That distinguishes them from most ( with the exception of   white blood cells   ) nonpluripotent cells. [151]   Obviously, changes in the glycosylation of outer membrane proteins are markers of the state of the cells connected in some way with pluripotency and differentiation. The "shift" in the nature of glycosylation, apparently, is not just the result of the initialization of some genes expression, but the mechanism performing the role of an important regulator of genes involved in the acquisition and maintenance of the undifferentiated state. [152]   For example, it is shown that activation of the glycoprotein ACA, [153]   linking glycosylphosphatidylinositol on the surface of the progenitor cells in human peripheral blood, induces increased expression of genes   Wnt ,   Notch-1 ,   BMI1   and   HOXB4 through a signaling cascade   PI3K / Akt / mTor / PTEN , and promotes the formation of self-renewing population of hematopoietic stem cells [154]   Furthermore, it is shown that dedifferentiation of progenitor cells induced by ACA- dependent signaling pathway leads to ACA- induced pluripotent stem cells, capable of differentiating in vitro into cells of all three   germ layers . [155]   The study of   lectins   on their ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin Erythrina Cristagalli (ECA), capable of serving as a simple and highly effective matrix for the cultivation of human pluripotent stem cells. [156]

Stimulus-triggered acquisition of pluripotency (STAP) cells

In   STAP , strong external stimuli such as a transient low-pH   stressor   reprogrammed mammalian somatic cells, produce pluripotent cells. STAP does not involve touching the DNA, nuclear transfer, or the introduction of transcription factors. [157]   Blastocyst injection showed that STAP cells efficiently contribute to chimaeric embryos and to offspring via germline transmission. STAP cells, unlike embryonic stem cells and iPSC, have only a limited capacity for self-renewal, but can contribute to both embryonic and placental tissues. Mouse STAP cells lose the ability to contribute to the placenta as well as trophoblast marker expression on converting into ES-like stem cells by treatment with adrenocorticotropic hormone   (ACTH) and   leukemia inhibitory factor   (LIF). In contrast, when cultured with Fgf4, STAP cells give rise to proliferative stem cells with enhanced trophoblastic characteristics. Unlike conventional trophoblast stem cells, the   Fgf4 -induced stem cells from STAP cells contribute to both embryonic and placental tissues in vivo and transform into ES-like cells (so-called STAP stem cells) when cultured with LIF-containing medium. [158]   Brain, skin, lung and liver cells have all been transformed using the technique. Conversion rates of 7.5% have been achieved, given that 25% of the cells survive the stress and 30% of those convert. Notably, three stressors — a bacterial toxin that perforates the cell membrane, exposure to low pH and physical squeezing — were each able to coax the cells to show markers of pluripotency. [159] [160]   It would be interesting to compare STAP cells with   Muse cells . [30] [31] [32] [33] [34]   It is known that Muse cells are easily reprogrammed to iPSC. [161] [162]   It is obvious that a strong stress activates in mature cells a natural repair and transdetermination processes that permit them to revert to their "naive" cell state. The remarkable properties demonstrated by STAP cells and STAP stem cells suggest that they could offer an unexpectedly simple and unobtrusive mechanism by which researchers can generate pluripotent cells for research—and perhaps even clinical—applications that previously required the laborious isolation of ES or iPS cells. [163]

Other labs are already trying to reproduce the work, and some have posted their experiences on a stem cell blog [164] . None has yet said they have successfully reprogrammed cells. Several scientists have contacted one or some of the authors for more details on the protocol without getting a response. Hongkui Deng, a stem-cell biologist at Peking University in Beijing, was told that “the authors will publish a detailed protocol soon”. Vacanti says he has had no problem repeating the experiment and says he will let Obokata supply the protocol “to avoid any potential for variation that could lead to confusion” [165]

Reprogramming through a physical approach

Cell adhesion protein   E-cadherin   is indispensable for a robust pluripotent phenotype. [166]   During reprogramming for iPS cell generation,   N-cadherin   can replace function of E-cadherin. [167]   These functions of cadherins obviously are not directly related to adhesion because, according to Guannan Su et al. [168]   sphere morphology helps maintaining the stemness of stem cells. Moreover, 3D sphere formation, due to forced growth of cells on low attachment surface, sometimes induces reprogramming. For example, neural progenitor cells can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors.

Physical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells’ epigenetic state. To be specific, as the authors of this study believe: "decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)—a subunit of H3 methyltranferase—by microgrooved surfaces lead to increased histone H3 acetylation and methylation". Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state. [169]

Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the   cytokine ,   leukemia inhibitory factor   (LIF). Following LIF withdrawal, mESCs differentiate, and this is accompanied by an increase in cell–substratum adhesion and cell spreading. Restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biomaterial substrates, or by manipulating the   cytoskeleton   allowed to keep the cells in an undifferentiated and pluripotent state. The effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as evidenced by the observations that inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA do not promote differentiation. [170]

The possible mechanisms of stem cell fate predetermining by physical interactions with the extracellular matrix see in reviews: [171] [172]

Induced neural stem cells (iNSCs)

Stroke and many neurodegenerative disorders such as: Parkinson's disease, Alzheimer’s disease, amyotrophic lateral sclerosis need cell replacement therapy. The successful use of converted neural cells (cNs) in transplantations open a new avenue to treat such diseases. [173]   Nevertheless, induced neurons (iNs), directly converted from fibroblasts are terminally committed neurons that exhibit very limited proliferative ability and may not provide enough autologous donor cells for transplantation. [174]   The generation of self-renewing induced neural stem cells (iNSCs) provides additional advantages over iNs for both basic research and clinical applications. [122] [123] [124] [175] [176]   For example, under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form induced neural stem cells (iNSCs) that self-renew in culture and after transplantation can survive, integrate and do not form tumors in mouse brains. [177]   Induced neural stem cells can also be derived from adult human fibroblasts by non-viral techniques, thus offering a safe method to generate iNSCs for autologous transplantation or for the development of cell-based disease models. [176]   Methods of direct transformation of somatic cells into induced neural stem cells differ in their technique as shown in the review. [178]

Some data provide proof of principle that it is possible, directly in the brain, to convert transplanted human fibroblasts and human astrocytes, which are engineered to express inducible forms of neural reprogramming genes, into neurons, when reprogramming genes (Ascl11, Brn2a, and Myt1l) are activated after transplantation using a drug in the animals’ drinking water. [179]   It was also shown that endogenous mouse astrocytes can be directly converted into neural nuclei (NeuN)-expressing neurons in situ.

Future studies will show which of these approaches proved to be most appropriate for clinic.

Oligodendrocyte precursor cells (OPCs)

Without myelin to insulate neurons, signals sent down nerve cell axons quickly lose power. Diseases that attack myelin, such as multiple sclerosis, result in nerve signals that are not efficient, because cannot propagate to nerve endings, and as a consequence to cognitive, motor, and sensory problems. Transplantation of oligodendrocyte precursor cells (OPCs), which can successfully create myelin sheaths around nerve cells, is a promising potential therapeutic strategy for diseases affecting myelin. However, there was no available source of engraftable OPCs. Therefore, direct lineage conversion of mouse and rat fibroblasts into oligodendroglial cells by forced expression of either eight [180]   or of the three [181]   transcription factors Sox10, Olig2 and Zfp536, laid the groundwork for therapies of a wide array of myelin disorders and spinal cord injury.

Induced cardiomyocytes (iCMs)

Development of regenerative therapeutic strategies to reverse the progression of advanced   heart failure   is one of the most urgent clinical needs of this century. Cell-based in vivo therapies may provide a transformative approach to augment vascular and muscle growth and to prevent non-contractile scar formation by delivering transcription factors [119]   or microRNAs [14]   to the heart. [182]   For example: Qian L. et al. & Srivastava D. demonstrate that cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be reprogrammed into   cardiomyocyte -like cells in vivo by local delivery of cardiac core transcription factors ( GATA4, MEF2C, TBX5 and for improved reprogramming plus ESRRG, MESP1, Myocardin and ZFPM2) after coronary ligation. [119] [183]   These results implicated therapies that can directly remuscularize the heart without the need for cell transplantation. However, the efficiency of direct cardiac reprogramming in vivo by overexpression of cardiac core transcription factors in cardiac fibroblasts turned out to be very low and phenotype of received cardiomyocyte-like cells does not resemble those of a bona fide mature cardiomyocyte. Furthermore, transplantation of cardiac transcription factors into injured murine hearts resulted in poor cell survival and minimal expression of cardiac genes. [184]   So, further technical improvements are needed to make this technology more applicable in situ. Meanwhile, there have been some advances in the methods of obtaining cardiac myocytes in vitro. [185]   For example, Carpenter et al. demonstrated efficient cardiac differentiation of human iPS cells that gave rise to progenitors that were retained within the infarcted rat heart, and reduced remodeling of the heart after ischemic damage. [186]   Furthermore, in ischaemic cardiomyopathy, caused by the murine infarction model, targeted iPS cell transplantation synchronized failing ventricles, offering a regenerative strategy to achieve resynchronization and protection from decompensation by dint of improved left ventricular conduction and contractility, reduced scar, and reversal of structural remodelling. [187]   Palecek S P et al., have developed a protocol for generating almost pure populations of cardiomyocytes (up to 98% cardiomyocytes) from human pluripotent stem cells simply by modulating canonical   Wnt signaling pathway   at defined time points in the differentiation process, using readily accessible small molecule compounds. [188]   Discovery of the mechanisms controlling the formation of cardiomyocytes led to the development of the drug (ITD-1), which effectively clears the cell surface from   TGF- β   receptor type II and selectively inhibits the intracellular TGF- β signaling and, thus, selectively enhances the differentiation of uncommitted   mesoderm   to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. [189]

Lu et al. [190]   create heart constructs by repopulating decellularized mouse hearts with human induced pluripotent stem cell-derived multipotential cardiovascular progenitor cells. They found that the seeded multipotential cardiovascular progenitor cells migrate, proliferate and differentiate in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the decellularized hearts. In addition, they observed that heart's extracellular matrix of mouse (the substrate of heart scaffold) can send signals to guide the repopulated human multipotential cardiovascular progenitor cells into becoming the specialised cells needed for proper heart function. After 20 days of perfusion with growth factors, the engineered heart tissues started to beat again and were responsive to drugs.

See also:   cell therapy in cardiovascular disease: selected research that has driven recent advances in clinical cardiology

Direct Reprogramming of Adult Cells to Nephron Progenitors (iNP)

Adult proximal tubule cells could be directly transcriptionally reprogrammed to   nephron   progenitors of the embryonic   kidney , using a pool of six genes of instructive transcription factors (SIX1, SIX2, OSR1, Eyes absent homolog 1(EYA1), Homeobox A11 (HOXA11) and Snail homolog 2 (SNAI2)) that activated a network of genes consistent with a cap mesenchyme/nephron progenitor phenotype in the adult proximal tubule cell line. [191]   The generation of such cells may lead to cellular therapies for adult   renal disease . Indeed, it has recently been shown that embryonic kidney organoids placed into adult rat kidney can undergo onward development and vascular development. [192]

Bioengineering of the cells of blood vessels

Blood vessels build extensive networks that supply all cells with nutrients and oxygen throughout life. As blood vessels get older, they often become abnormal in structure and function, thereby contributing to numerous age-associated diseases including myocardial infarction, ischemic stroke and atherosclerosis of arteries supplying the heart, brain, and lower extremities. So, an important goal is to stimulate vascular growth for the   collateral circulation   to prevent the exacerbation of these diseases. A useful cell type for cell-based therapy designed to stimulate coronary collateral growth are Induced Vascular Progenitor Cells (iVPCs), generated by partially reprogramming endothelial cells. [150]   The vascular commitment of iVPCs is related to the epigenetic memory of endothelial cells, which engenders them as cellular components of growing blood vessels. That is why, when iVPCs were implanted into myocardium, they engrafted in blood vessels and increased coronary collateral flow better than iPSCs, mesenchymal stem cells, or native endothelial cells. [193]   An effective strategy to enhance stem cell function is ex vivo genetic modification. For example, genetic modification with Pim-1 kinase (a downstream effector of Akt, which positively regulates neovasculogenesis) of bone marrow–derived cells [194]   or human cardiac progenitor cells, isolated from failing myocardium [195]   results in durability of repair, together with the superior improvement of functional parameters of myocardial hemodynamic performance after cellular therapy of the injured myocardium with modified progenitor cells. Stem cells extracted from fat tissue after   liposuction   may be coaxed into progenitor smooth muscle   cells (iPVSMCs) found in arteries and veins. [196]   In the future, iVPCs and iPVSMCs may become a necessary source for the creation of blood vessels networks for tissue engineering and reconstruction of organs for transplantation. For instance, it was found that the 2D culture system of human iPS cells [197]   in conjunction with the CD34 (a surface glycophosphoprotein expressed on developmentally early embryonic fibroblast), NP1 (receptor - neuropilin 1) and KDR (kinase insert domain-containing receptor) triple marker selection (for the isolation of vasculogenic precursor cells from human induced pluripotent stem cells) was capable to generate endothelial cells that, after transplantation, were able to form stable functional blood vessels in vivo, lasting for 280 d in mice. [198]

In the treatment of infarction, it is important to prevent the formation of fibrotic scar tissue. This can be achieved in vivo by means of transient application of paracrine factors changing the fate of the native heart progenitor stem cells from contributing to cardiac fibrotic scar tissue and toward cardiovascular tissue. For example, it was shown in a mouse myocardial infarction model that a single intramyocardial injection of human vascular endothelial growth factor-A mRNA (VEGF-A modRNA), synthetically modified so that it escapes the normal defense system of the body, results in long-term improvement of heart function due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types   [199]

Bioengineering of blood stem cells

Definitive hematopoiesis emerges during embryogenesis via an endothelial-to-hematopoietic transition. Fairly simple combination of four transcription factors, Gata2, Gfi1b, cFos, and Etv6, is sufficient to induce in vitro this complex, dynamic, and multistep developmental program leading to the formation of endothelial-like precursor cells, with the subsequent appearance of hematopoietic cells. [200]

Red blood cells (RBC)

Red blood cells   (RBC)   transfusion   is necessary for many patients with emergency or hematological disorders. However, to date the supply of RBCs remains labile and dependent on voluntary donations. In addition, the transmission of infectious disease via blood transfusion from unspecified donors remains a risk. Establishing a large quantity of safe RBCs would help to address this issue. New technologies for ex vivo erythroid cell generation will hopefully provide alternative transfusion products to meet present and future clinical requirements. [201] [202]   In favor of this suggest data that RBCs generated in vitro from mobilized   CD34   positive cells have normal survival when transfused into an autologous recipient. [203]   However, the RBC produced in vitro contained exclusively fetal hemoglobin (HbF), which rescues the functionality of these RBCs. However, in vivo the switch of fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from induced pluripotent stem cells was observed. [204]   But then there is another problem: although RBCs do not have nuclei, and therefore can not form a tumor, their immediate precursors the erythroblasts do. The terminal maturation of erythroblasts into functional RBCs requires a complex remodeling process that ends with extrusion of the nucleus and the formation of an enucleated RBC. [205]   Alas, cell reprogramming methodologies at present often disrupt these processes of enucleation, and therefore transfusion of in vitro-generated RBCs or their immediate precursors the erythroblasts still insufficiently protected against the possibility of tumors formation. However, Bouhassira and colleagues recently found that exposing CD34 positive cells to a short pulse of cytokines favorable for erythroid differentiation prior to stem cell expansion followed by progenitor expansion produced on the order more yield of erythroid cells than the yields observed previously. And the most important: These red blood cells expressed a globin profile similar to that of the developmental age of the CD34 positive cells [206]   It is also interesting to note that an important role in normal blood cell development plays the aryl hydrocarbon receptor (AhR) pathway (which has been shown to be involved in the promotion of cancer cell development). AhR activation in human hematopoietic progenitor cells (HPs) drives an unprecedented expansion of HPs, megakaryocyte- and erythroid-lineage cells. [207]

See also: Migliaccio AR, Whitsett C, Papayannopoulou T, Sadelain M. (2012)   The potential of stem cells as an in vitro source of red blood cells for transfusion.   Review. Cell Stem Cell.;10(2):115-9


Platelets   play an important role in preventing hemorrhage in thrombocytopenic patients and patients with thrombocythemia. A significant problem for multitransfused patients is refractoriness to platelet transfusions. Thus, the ability to generate platelet products ex vivo and platelet products lacking   HLA antigens   in serum free media, would have great clinical value. Some success in this direction has achieved Figueiredo et al. Using an   RNA interference -based mechanism in which a   lentiviral vector   was used to express short-hairpin RNAi targeting  β 2-microglobulin transcripts in CD34-positive cells, they generated platelets demonstrating an 85% reduction in class I HLA antigens. These platelets appeared to have normal function in vitro [208]   A clinically applicable strategy for the derivation of functional platelets from human iPSC was developed, that involves the establishment of stable immortalized megakaryocyte progenitor cell lines (imMKCLs) through the   doxycycline -dependent overexpression of   BMI1   and   BCL-XL . The resulting imMKCLs can be expanded in culture over extended periods (4–5 months), even after cryopreservation. Halting the overexpression (by the removal of doxycycline from the medium) of c-MYC,   BMI1 , and   BCL-XL   in growing imMKCLs led to the production of   CD42b + platelets with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo. [209]

Immune cells

A specialised type of   white blood cell , known as   cytotoxic T   lymphocytes   (CTLs) , are produced by the   immune system   and are able to recognise specific markers on the surface of various infectious or tumour cells, causing them to launch an attack to kill the harmful cells. Thence, immunotherapy with functional antigen-specific T cells has potential to be an effective therapeutic strategy for combating many types of cancer and viral infection. [210]   However, sources of such cells for therapeutic purposes are limited, because they are produced in small numbers naturally and have a short lifespan. A potentially efficient approach for generating antigen-specific CTLs is to revert mature immune T cells into iPSCs, which possess indefinite proliferative capacity in vitro, and after their multiplication to coaxed them to redifferentiate back into T cells [211] [212] [213] [214]   Even more opportunities promises a method that combine iPSC and chimeric antigen receptor (CAR)   [215]   technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture. [216]   This approach of generating therapeutic human T cells 'in the dish' may be useful for cancer immunotherapy and other medical applications because such 'living drugs' have fewer side-effects, once injected - stay in the body and move around to stop recurrences.

Invariant   natural killer T   (iNKT) cells   has great clinical potential as   adjuvant   for cancer immunotherapy. iNKT cells act as innate T lymphocytes and serve as a bridge between the   innate   and   acquired immune systems . They augment anti-tumor responses by producing   interferon-gamma   (IFN- γ ). [217]   A conceptual method is proposed for the use of iPSC-derived iNKT cells for adjuvant cell therapy against cancer, which is composed of four segments: (1) collection of iNKT cells, (2) reprogramming of iNKT cells into iPSCs, (3) re-differentiation of iNKT cell-derived iPSCs into iNKT cells and their expansion in vitro, and (4) injection of iPSC-derived iNKT cells into tumor-bearing animals. [218]

Dendritic cells   (DC)   are specialized to control T-cell responses. DC with appropriate genetic modifications may survive long enough to stimulate antigen-specific CTL and, after that, be completely eliminated. It was shown that DC-like antigen-presenting cells obtained from human induced pluripotent stem cells may serve as an unlimited source for   vaccination   therapy. [219]

B cells .   CCAAT/enhancer binding protein- α (C/EBP α )   induces transdifferentiation of   B cells   into   macrophages   at high efficiencies [220] [221]   and enhances reprogramming into iPS cells when co-expressed with the transcription factors Oct4, Sox2, Klf4 and Myc [222]   with a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population. [223]   Furthermore, C/EBPa can convert at high efficiencies selected human B cell lymphoma and leukemia cell lines into macrophage-like cells, impairing the cells’ tumor-forming capacity. [224]

Induced Mesenchymal stem cells (iMSCs)

Induction of human iPSc to Generate Mesenchymal Stem/Stromal Cells

Because of their immunosuppressive properties and ability to differentiate into a wide range of mesenchymal-lineage tissues, mesenchymal stem/stromal cells   (MSCs) are under intense investigation for applications in cardiac, renal, neural, joint, and bone repair, as well as in inflammatory conditions and hemopoietic cotransplantation. [225]   MSCs are typically harvested from adult bone marrow or fat, but these not only require painful invasive procedures but are low-frequency sources, with MSCs making up only 0.001%– 0.01% of bone marrow cells and 0.05% in liposuction aspirates. [226]   Of concern for autologous use, in particular in the elderly most in need of tissue repair, MSCs decline in quantity and quality with age. [225] [227] [228]   However, induced pluripotent stem cells (iPSCs) could be obtained by the cells rejuvenation of even centenarian human. [9]   Because iPSCs can be harvested free of ethical constraints and culture can be expanded indefinitely, they are an advantageous source of MSCs. [229]   Chen and colleagues discovered that iPSCs treatment with   SB-431542   (that inhibits the activin/TGF- pathways by blocking phosphorylation of ALK4, ALK5, and ALK7 receptors) leads to rapid and uniform MSC generation from human iPSCs. These iPS-MSCs possibly lack teratoma-forming ability, display a normal stable karyotype in culture, and exhibit growth and differentiation characteristics that closely resemble those of primary MSCs described, has considerable potential for the in vitro scale-up required to enable a wide range of MSC-based therapies. [230]   Unfortunately, currently there is no data on the in vivo efficacy and long-term safety of iPSC-derived MSCs generated by this method.

It is interesting to note that besides cell therapy in vivo the culture of human mesenchymal stem cells can be used in vitro for mass-production of   exosomes , which, as it turned out, are ideal vehicles for drug delivery. [231] [232] [233] [234]

Dedifferentiated adipocytes: an alternative source of MSC

Adipose tissue, because of its abundance and relatively less invasive harvest methods, represents a practical and appealing source of mesenchymal stem cells (MSCs). Unfortunately, there are only 0.05% MSCs in liposuction aspirates. [226]   However, a large amount of mature adipocytes, which, in general, lost their proliferative abilities, and therefore often discarded, can be easily isolated from the adipose cell suspension and dedifferentiated into lipid-free fibroblast-like cells, named dedifferentiated fat (DFAT) cells. DFAT cells re-establish active proliferation ability and undertake multipotent capacities. [235]   Compared with adult stem cells, DFAT cells showed unique advantages in their abundance, isolation, and homogeneity. Under proper induction culture in vitro or environment in vivo, DFAT cells could demonstrate adipogenic, osteogenic, chondrogenic, and myogenic potentials. They also could exhibit perivascular characteristics and elicit neovascularization. [236] [237] [238]

Induced chondrogenic cells (iChon cells)

Cartilage is the connective tissue responsible for frictionless joint movement. Its degeneration ultimately results in complete loss of joint function in the late stages of osteoarthritis. As an avascular and hypocellular tissue, cartilage has a very limited capacity for self-repair. Chondrocytes are the only cell type in cartilage, in which they are surrounded by the extracellular matrix that they secrete and assemble. One conceivable method of producing cartilage is to induce it from iPS cells. [239]   Alternatively, it is possible to convert fibroblasts directly into induced chondrogenic cells (iChon cells) without an intermediate iPS cell stage, by inserting three reprogramming factors (c-MYC, KLF4, and SOX9). [240]   The human iChon cells expressed marker genes for chondrocytes (type II collagen) but not fibroblasts. Implanted into defects created in the articular cartilage of rats’, the human iChon cells were able to survive and form cartilaginous tissue for at least four weeks, but not tumors. Nevertheless, the method used in the study makes use of c-MYC, which is thought to have a major role in tumorigenesis, and employs a retrovirus to introduce the reprogramming factors. So, it could not be applied without modification in human therapy.

Sources of cells for reprogramming

The most frequently used source for reprogramming are blood cells. [241] [242] [243] [244]   and fibroblasts, obtained by biopsy of the skin, [245]   but more convenient to receive the body cells from the urine. [246] [247] [248] [249]   This method does not require a biopsy or blood sampling and therefore harmless to the patient. Urine-derived stem cells have capacity for multipotent differentiation. They are able to differentiate into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic and neurogenic lineages, but did not form teratomas. [250]   Therefore, their epigenetic memory better suited to the reprogramming into iPS cells. However, there are very few cells in the urine, the efficiency of turning them into induced stem cells is low, whereas the risk of bacterial contamination higher than with other sources of cells.

Another promising source of cells for reprogramming are mesenchymal stem cells derived from human hair follicles. [251]

It is important to note that the origin of somatic cells used for reprogramming may influence the efficiency of reprogramming, [252] [253] the functional properties of the resulting induced stem cells [254]   and the ability to form tumors. [255] [256]

While selecting the source for reprogramming, into account should be taken the fact that iPSCs retain an epigenetic memory of their tissue of origin, and that this impacts their differentiation potential [213] [254] [257] [258] [259] [260]   This epigenetic memory does not necessarily manifest itself at the pluripotency stage – iPSCs derived from different tissues exhibit proper morphology, express pluripotency markers, and are able to differentiate into the three embryonic layers in vitro and in vivo. However, this epigenetic memory may manifest later, during re-differentiation into specific cell types that require the specific loci that have residual epigenetic marks.

References for further reading

·                      Tabar, V., & Studer, L. (2014). Pluripotent stem cells in regenerative medicine: challenges and recent progress .  Nature Reviews Genetics, 15(2), 82-92. doi:10.1038/nrg3563

·                      Tan, Y., Ooi, S., & Wang, L. (2014). Immunogenicity and Tumorigenicity of Pluripotent Stem Cells and their Derivatives: Genetic and Epigenetic Perspectives .Current stem cell research & therapy, 9(1), 63-72

·                      Shinya Yamanaka (2012)   Induced Pluripotent Stem Cells: Past, Present, and Future.   Cell Stem Cell, 10(6), 678-684, 10.1016/j.stem.2012.05.005

·                      Kazutoshi Takahashi and Shinya Yamanaka (2013) Induced pluripotent stem cells in medicine and biology.  Development, 140, 2457-2461.   doi : 10.1242/dev.092551

·                      Grace E. Asuelime and Yanhong Shi (2012)   A case of cellular alchemy: lineage reprogramming and its potential in regenerative medicine   J Mol Cell Biol doi: 10.1093/jmcb/mjs005

·                      Lensch, M. W., & Mummery, C. L. (2013)   From Stealing Fire to Cellular Reprogramming: A Scientific History Leading to the 2012 Nobel Prize .  Stem Cell Reports, 1(1), 5-17   doi : 10.1016/j.stemcr.2013.05.001

·                      Special Issue (October 2013)   Induced Pluripotent Stem Cells .  Genomics, Proteomics & Bioinformatics. 11(5), 257-334

·                      Ji Lin, Mei-rong Li, Dong-dong Ti, et al. & Wei-dong Han (2013)   Microenvironment-evoked cell lineage conversion: Shifting the focus from internal reprogramming to external forcing   Review Article.  Ageing Research Reviews

·                      Takahashi K. (2012)   Cellular reprogramming – lowering gravity on Waddington's epigenetic landscape.   J Cell Sci.; 125 (11), 2553-2560. doi: 10.1242/jcs.084822

·                      Nobel Prize in Physiology or Medicine 2012 Awarded for Discovery That Mature Cells Can Be Reprogrammed to Become Pluripotent

·                      Samer MI Hussein, Andras A Nagy (2012)   Progress made in the reprogramming field: new factors, new strategies and a new outlook.   Current Opinion in Genetics & Development. 22(5), 435–443   http://dx.doi.org/10.1016/j.gde.2012.08.007

·                      Yemin Zhang, Lin Yao, Xiya Yu, Jun Ou, Ning Hui and Shanrong Liu (2012)   A poor imitation of a natural process: A call to reconsider the iPSC engineering technique.   Cell Cycle, 11(24), 4536 - 4544

·                      Ignacio Sancho-Martinez, Sung Hee Baek & Juan Carlos Izpisua Belmonte (2012)   Lineage conversion methodologies meet the reprogramming toolbox .  Nature Cell Biology, 14, 892–899 doi:10.1038/ncb2567

·                      Mochiduki, Y. and Okita, K. (2012)   Methods for iPS cell generation for basic research and clinical applications .  Biotechnology Journal, 7: 789–797. doi: 10.1002/biot.201100356

·                      Rosalinda Madonna (2012)   Human-Induced Pluripotent Stem Cells: In Quest of Clinical Applications   Molecular Biotechnology, 52(2), 193-203 DOI: 10.1007/s12033-012-9504-0

·                      M. Lorenzo, A. Fleischer, D. Bachiller (2012)   Generation of Mouse and Human Induced Pluripotent Stem Cells (iPSC) from Primary Somatic Cells . Stem Cell Reviews and Reports DOI 10.1007/s12015-012-9412-5 (detailed protocols & all-encompassing instructions)

·                      Detailed protocols for reprogramming and for analysis of iPSCs

·                      Buganim, Y., Faddah, D. A., & Jaenisch, R. (2013) Mechanisms and models of somatic cell reprogramming.  Nature Reviews Genetics, 14(6), 427-439. doi: 10.1038/nrg3473 researchgate.net [PDF]


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