World Library  
Flag as Inappropriate
Email this Article

Induced stem cells

Article Id: WHEBN0036315057
Reproduction Date:

Title: Induced stem cells  
Author: World Heritage Encyclopedia
Language: English
Subject: Tissue engineering, Cell potency, Induced pluripotent stem cell, Induced stem cells, Clone (cell biology)
Publisher: World Heritage Encyclopedia

Induced stem cells

Induced stem cells (iSC) are stem cells artificially derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor (multipotent—iMSC, also called an induced multipotent progenitor cell—iMPC) or unipotent -- (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

Three techniques are widely recognized:[1]

Natural processes of induction

Back in 1895, frog blastomeres and found that amphibians are able to form whole embryo from the remaining part. This meant that the cells can change their differentiation pathway. Later, in 1924, Spemann and Mangold demonstrated the key importance of cell–cell inductions during animal development.[20] The reversible transformation of cells of one differentiated cell type to another is called metaplasia.[21] This transition can be a part of the normal maturation process, or caused by an inducing stimulus. For example: transformation of iris cells to lens cells in the process of maturation and transformation of retinal pigment epithelium cells into the neural retina during regeneration in adult newt eyes. This process allows the body to replace cells not suitable to new conditions with more suitable new cells. In Drosophila imaginal discs, cells have to choose from a limited number of standard discrete differentiation states. The fact that transdetermination (change of the path of differentiation) often occurs for a group of cells rather than single cells shows that it is induced rather than part of maturation.[22]

The researchers were able to identify the minimal conditions and factors that would be sufficient for starting the cascade of molecular and cellular processes to instruct pluripotent cells to organize the in vivo or in vitro, uncommitted cells of the zebrafish blastula animal pole into a well-developed embryo.[23]

Some types of mature, specialized adult cells can naturally revert to stem cells. For example, "chief" cells express the stem cell marker Troy. While they normally produce digestive fluids for the stomach, they can revert into stem cells to make temporary repairs to stomach injuries, such as a cut or damage from infection. Moreover, they can make 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.[24] Differentiated airway epithelial cells can revert into stable and functional stem cells in vivo.[25]

Cluster forming of pluripotent Muse/Stem cell

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[26] Macrophages can self-renew by local proliferation of mature differentiated cells.[27] In newts, muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget the type of cell they had been. This capacity to regenerate does not decline with age and may be linked to their ability to make new stem cells from muscle cells on demand.[28]

A variety of nontumorigenic stem cells display the ability to generate multiple cell types. For instance, multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant adult human stem cells that can self-renew. They 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.[29][30][31][32][33]

Other well-documented examples of transdifferentiation and their significance in development and regeneration were described in detail.[34]

Induced totipotent cells usually can be obtained by reprogramming somatic cells by somatic-cell nuclear transfer (SCNT).

Induced totipotent cells


Induced totipotent cells can be obtained by reprogramming somatic cells with somatic-cell nuclear transfer (SCNT). The process involves sucking out the nucleus of a somatic (body) cell and injecting it into an oocyte that has had its nucleus removed[3][5][35][36]

Using an approach based on the protocol outlined by Tachibana et al.,[3] hESCs can be generated by SCNT using dermal fibroblasts nuclei from both a middle-aged 35-year-old male and an elderly, 75-year-old male, suggesting that age-associated changes are not necessarily an impediment to SCNT-based nuclear reprogramming of human cells.[37] Such reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine. Unfortunately, the cells generated by this technology, potentially are not completely protected from the immune system of the patient (donor of nuclei), because they have the same mitochondrial DNA, as a donor of oocytes, instead of the patients mitochondrial DNA. This reduces their value as a source for autologous stem cell transplantation therapy, as for the present, it is not clear whether it can induce an immune response of the patient upon treatment.

Induced androgenetic haploid embryonic stem cells can be used instead of sperm for cloning. These cells, synchronized in M phase and injected into the oocyte can produce viable offspring.[38]

These developments, together with data on the possibility of unlimited oocytes from mitotically active reproductive stem cells,[39] offer the possibility of industrial production of transgenic farm animals. Repeated recloning of viable mice through a SCNT method that includes a histone deacetylase inhibitor, trichostatin, added to the cell culture medium,[40] show that it may be possible to reclone animals indefinitely with no visible accumulation of reprogramming or genomic errors[41] However, research into technologies to develop sperm and egg cells from stem cells raises bioethical issues.[42]

Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes.[3][43] For example, the technology could prevent inherited mitochondrial disease from passing to future generations. Mitochondrial genetic material is passed from mother to child. Mutations can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and other neurological diseases. The nucleus from one human egg has been transferred to another, including its mitochondria, 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.[44] As evidence that the technique is safe author of this method points to the existence of the healthy monkeys that are now more than four years old — and are the product of mitochondrial transplants across different genetic backgrounds.[45]

In late-generation telomerase-deficient (Terc−/−) mice, SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming.[46]

Other cloning and totipotent transformation achievements have been described.[47]

Obtained without SCNT

Recently some researchers succeeded to get the totipotent cells without the aid of SCNT. Totipotent cells were obtained using the epigenetic factors such as oocyte germinal isoform of histone.[48] Reprogramming in vivo, by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice, confers totipotency features. Intraperitoneal injection of such in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic (trophectodermal) markers.[49]

Rejuvenation to iPSc

Transplantation of pluripotent/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. However, putting teratocarcinoma cells into the embryo at the blastocyst stage, caused them to become incorporated in the cell mass and often produced a normal healthy chimeric (i.e. composed of cells from different organisms) animal

iPSc were first obtained in the form of transplantable [57][58][59] This indicated that the cause of the teratoma is a dissonance - mutual miscommunication between young donor cells and surrounding adult cells (the recipient's so-called "niche").

In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic fibroblasts into pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc, they proved that the overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes.[7]

Human somatic cells are made pluripotent by transducing them with factors that induces pluripotency (OCT 3/4, SOX2, Klf4, c-Myc, NANOG and LIN28). This results in the production of IPS cells, which can differentiate into any cells of the three embryonic germ layers (Mesoderm, Endoderm, Ectoderm).

Reprogramming mechanisms are thus linked, rather than independent and are centered on a small number of genes.[60] IPSC properties are very similar to ESCs. iPSCs have been shown to support the development of all-iPSC mice using a tetraploid (4n) embryo,[61] the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to produce all-iPSC mice because of aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster.[18]

An important advantage of iPSC over ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adult and even elderly patients.[9][62][63]

Reprogramming somatic cells to iPSC leads to rejuvenation. It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into fibroblast-like derivatives.[64] Thus, reprogramming leads to the restoration of embryonic telomere length,[65] and hence increases the potential number of cell divisions otherwise limited by the Hayflick limit.[66]

However, because of the dissonance between rejuvenated cells and the surrounding niche of the recipient's older cells, the injection of his own iPSC usually leads to an immune response,[67] which can be used for medical purposes,[68] or the formation of tumors such as teratoma.[69] The reason has been hypothesized to be that some cells differentiated from ESC and iPSC in vivo continue to synthesize embryonic protein isoforms.[70] So, the immune system might detect and attack cells that are not cooperating properly.

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. Shortly after differentiation, daughter cells became resistant to death. When MitoBloCK-6 was introduced to differentiated cell lines, the cells remained healthy. The key to their survival, was hypothesized to 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 has the potential to reduce the risk of teratomas and other problems in regenerative medicine.[71]

In 2012 other small molecules (selective cytotoxic inhibitors of human pluripotent stem cells—hPSCs) were identified that prevented human pluripotent stem cells from forming teratomas in mice. 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.[72] 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). A single treatment with chemical survivin inhibitors (e.g., quercetin or YM155) can induce selective and complete cell death of undifferentiated hPSCs and is claimed to be sufficient to prevent teratoma formation after transplantation.[73] However, it is unlikely that any kind of preliminary clearance,[74] is able to secure the replanting iPSC or ESC. After the selective removal of pluripotent cells, they re-emerge quickly by reverting differentiated cells into stem cells, which leads to tumors.[75] 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 micro-RNA miRNA loss.[76]

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.[77] These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells.[78] In connection with the above safety problems, the use iPSC for cell therapy is still limited.[79] However, they can be used for a variety of other purposes - including the modeling of disease,[80] screening (selective selection) of drugs, toxicity testing of various drugs.[81]

Small molecule modulators of stem-cell fate.

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 [49] Furthermore, partial reprogramming of cells toward pluripotency in vivo in mice demonstrates that incomplete reprogramming entails epigenetic changes (failed repression of Polycomb targets and altered DNA methylation) in cells that drive cancer development.[83]

Cell culture example of a small molecule as a tool instead of a protein. in cell culture to obtain a pancreatic lineage from mesodermal stem cells the retinoic acid signalling pathway must be activated while the sonic hedgehog pathway inhibited, which can be done by adding to the media anti-shh antibodies, Hedgehog interacting protein or cyclopamine, the first two are protein and the last a small molecule.[84]

Chemical inducement

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.[85]

Differentiation from induced teratoma

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[86] 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).[87] 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 [71] and / or PluriSIn # 1 the differentiated progenitor cells can be further purified from teratoma forming pluripotent cells. The fact, that the differentiation takes place even in the teratoma niche, 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.[88] 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.[89]

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 CTLA4-Ig, which disrupts T cell costimulatory pathways, and PD-L1, which activates T cell inhibitory pathway.[91]

See also: US 20130058900  patent.

Differentiated cell types

Retinal cells

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[92] [93] and how to use them for cell therapy.[94] Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced visual-guided behaviors of experimental animals for 6 weeks after transplantation.[95] 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. [96]

Lung and airway epithelial cells

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.[97][98] 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.[99]

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.[100]

Induced progenitor stem cells

Direct transdifferentiation

The risk of cancer and tumors creates the need to develop methods for safer cell lines suitable for clinical use. An alternative approach is so-called "direct reprogramming" - transdifferentiation of cells without passing through the pluripotent state.[101][102][103][104][105][106] The basis for this approach was that 5-azacytidine - a DNA demethylation reagent - can cause the formation of myogenic, chondrogenic and adipogeni] clones in the immortal cell line of mouse embryonic fibroblasts[107] and that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming.[108] Compared with iPSC whose reprogramming requires at least two weeks, the formation of induced progenitor cells sometimes occurs within a few days and the efficiency of reprogramming is usually many times higher. This reprogramming does not always require cell division.[109] The cells resulting from such reprogramming are more suitable for cell therapy because they do not form teratomas.[106]

Single transcription factor transdifferentiation

Originally only early embryonic cells could be coaxed into changing their identity. Mature cells are resistant to changing their identity once they've committed to a specific kind. However, brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, specialized non-endodermal cells of the pharynx into fully differentiated intestinal cells in intact larvae and adult roundworm Caenorhabditis elegans with no requirement for a dedifferentiated intermediate.[110]

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 into limb tissue. 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.[111]

Antibody-based transdifferentiation

The researchers discovered that GCSF-mimicking antibody can activate a growth-stimulating receptor on marrow cells in a way that induces marrow stem cells that normally develop into white blood cells to become neural progenitor cells. The technique[112] enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect.[113]

Conditionally reprogrammed cells

Schlegel and Liu[114] demonstrated that the combination of feeder cells[115][116][117] and a Rho kinase inhibitor (Y-27632) [118][119] induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro. This process occurs without the need for transduction of exogenous viral or cellular genes. These cells have been termed "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population. 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.[114][120][121] CRC technology can generate 2×106 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.[114][122][123]

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.[114][122][123] Using CRC technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor.[124] 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 initial studies revealed that co-culturing epithelial cells with Swiss 3T3 cells J2 was essential for CRC induction, with transwell culture plates, physical contact between feeders and epithelial cells is not required for inducing CRCs, and more importantly that irradiation of the feeder cells is required for this induction. Consistent with the transwell experiments, conditioned medium induces and maintains CRCs, which is accompanied by a concomitant increase of cellular telomerase activity. The activity of the conditioned medium correlates directly with radiation-induced feeder cell apoptosis. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells.[125]

Riegel et al. [126] demonstrate that mouse ME cells isolated from normal mammary glands or from mouse mammary tumor virus (MMTV)-Neu–induced mammary tumors, can be cultured indefinitely as conditionally reprogrammed cells (CRCs). Cell surface progenitor-associated markers are rapidly induced in normal mouse ME-CRCs relative to ME cells. However, the expression of certain mammary progenitor subpopulations, such as CD49f+ ESA+ CD44+, drops significantly in later passages. Nevertheless, mouse ME-CRCs grown in a three-dimensional extracellular matrix gave rise to mammary acinar structures. ME-CRCs isolated from MMTV-Neu transgenic mouse mammary tumors express high levels of HER2/neu, as well as tumor-initiating cell markers, such as CD44+, CD49f+, and ESA+ (EpCam). These patterns of expression are sustained in later CRC passages. Early and late passage ME-CRCs from MMTV-Neu tumors that were implanted in the mammary fat pads of syngeneic or nude mice developed vascular tumors that metastasized within 6 weeks of transplantation. Importantly, the histopathology of these tumors was indistinguishable from that of the parental tumors that develop in the MMTV-Neu mice. Application of the CRC system to mouse mammary epithelial cells provides an attractive model system to study the genetics and phenotype of normal and transformed mouse epithelium in a defined culture environment and in vivo transplant studies.

A different approach to CRC is to inhibit CD47 - a membrane protein that is the thrombospondin-1 receptor. 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. 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.[127] 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.[128]

Indirect lineage conversion

Indirect lineage conversion is a reprogramming methodology 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 in a specially developed chemical environment (artificial niche).[129]

This 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 remains questionable. Since lineage conversion from pre-iPSC relies on the use of iPSC reprogramming conditions, 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.[130]

Outer membrane glycoprotein

A common feature of pluripotent stem cells is the specific nature of protein glycosylation of their outer membrane. That distinguishes them from most nonpluripotent cells, although not white blood cells.[131] The glycans on the stem cell surface respond rapidly to alterations in cellular state and signaling and are therefore ideal for identifying even minor changes in cell populations. Many stem cell markers are based on cell surface glycan epitopes including the widely used markers SSEA-3, SSEA-4, Tra 1-60, and Tra 1-81.[132] Suila Heli et al.[133] speculate that in human stem cells extracellular O-GlcNAc and extracellular O-LacNAc, play a crucial role in the fine tuning of Notch signaling pathway - a highly conserved cell signaling system, that regulates cell fate specification, differentiation, left–right asymmetry, apoptosis, somitogenesis, angiogenesis, and plays a key role in stem cell proliferation (reviewed by Perdigoto and Bardin[134] and Jafar-Nejad et al.[135])

Changes in outer membrane protein glycosylation are markers of cell states connected in some way with pluripotency and differentiation.[136] The glycosylation change is apparently not just the result of the initialization of gene expression, but perform as an important gene regulator involved in the acquisition and maintenance of the undifferentiated state.[137]

For example, activation of glycoprotein ACA,[138] 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 a self-renewing population of hematopoietic stem cells.[139]

Furthermore, 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.[140] The study of lectins' ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin Erythrina crista-galli (ECA), which can serve as a simple and highly effective matrix for the cultivation of human pluripotent stem cells.[141]

Reprogramming through a physical approach

Cell adhesion protein E-cadherin is indispensable for a robust pluripotent phenotype.[142] During reprogramming for iPS cell generation, N-cadherin can replace function of E-cadherin.[143] These functions of cadherins are not directly related to adhesion because sphere morphology helps maintaining the "stemness" of stem cells.[144] Moreover, sphere formation, due to forced growth of cells on a 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. Specifically, "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.[145]

Role of cell adhesions in neural development. Image courtesy of WorldHeritage user JWSchmidt under the GNU Free Documentation License

Substrate rigidity is an important biophysical cue influencing neural induction and subtype specification. For example, soft substrates promote neuroepithelial conversion while inhibiting neural crest differentiation of hESCs in a BMP4-dependent manner. Mechanistic studies revealed a multi-targeted mechanotransductive process involving mechanosensitive Smad phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and actomyosin cytoskeleton integrity and contractility.[146]

Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the cytokine leukemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, 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 biosubstrates, or by manipulating the cytoskeleton allowed the cells to remain in an undifferentiated and pluripotent state. The effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA does not promote differentiation.[147] Possible mechanisms of stem cell fate predetermination by physical interactions with the extracellular matrix have been described.[148]

Microfluidic device made of glass

Cells involved in the reprogramming process change morphologically as the process proceeds. This results in physical difference in adhesive forces among cells. Substantial differences in 'adhesive signature' between pluripotent stem cells, partially reprogrammed cells, differentiated progeny and somatic cells allowed to develop separation process for isolation of pluripotent stem cells in microfluidic devices,[149] which is: • fast (separation takes less than 10 minutes); • efficient (separation results in a greater than 95 percent pure iPS cell culture); • innocuous (cell survival rate is greater than 80 percent and the resulting cells retain normal transcriptional profiles, differentiation potential and karyotype).

Stem cells possess mechanical memory (they remember past physical signals)—with the Hippo signaling pathway factors:[150] Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) acting as an intracellular mechanical rheostat—that stores information from past physical environments and influences the cells’ fate.[151][152]

Neural stem cells

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.[153] Nevertheless, induced neurons (iNs), directly converted from fibroblasts are terminally committed and exhibit very limited proliferative ability that may not provide enough autologous donor cells for transplantation.[154] Self-renewing induced neural stem cells (iNSCs) provide additional advantages over iNs for both basic research and clinical applications.[104][105][106][155][156]

For example, under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form iNSCs that self-renew in culture and after transplantation can survive and integrate without forming tumors in mouse brains.[157] INSCs can be derived from adult human fibroblasts by non-viral techniques, thus offering a safe method for autologous transplantation or for the development of cell-based disease models.[156]

Neural chemically induced progenitor cells (ciNPCs) can be generated from mouse tail-tip fibroblasts and human urinary somatic cells without introducing exogenous factors, but - by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, RepSox, an inhibitor of TGF beta signaling pathways), under a physiological hypoxic condition.[158] Alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase, and TGF-β pathways (where: sodium butyrate (NaB) or Trichostatin A (TSA) could replace VPA, Lithium chloride (LiCl) or lithium carbonate (Li2CO3) could substitute CHIR99021, or Repsox may be replaced with SB-431542 or Tranilast) show similar efficacies for ciNPC induction.[158]

Multiple methods of direct transformation of somatic cells into induced neural stem cells have been described.[159]

Proof of principle experiments demonstrate that it is possible to convert transplanted human fibroblasts and human astrocytes directly in the brain that are engineered to express inducible forms of neural reprogramming genes, into neurons, when reprogramming genes (Ascl1, Brn2a and Myt1l) are activated after transplantation using a drug.[160]

Astrocytes—the most common neuroglial brain cells, which contribute to scar formation in response to injury—can be directly reprogrammed in vivo to become functional neurons that formed networks in mice without the need of cell transplantation.[161] The researchers followed the mice for nearly a year to look for signs of tumor formation and reported finding none. The same researchers have turned scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons in the injured adult spinal cord.[162]

Oligodendrocyte precursor cells

Without myelin to insulate neurons, nerve signals quickly lose power. Diseases that attack myelin, such as multiple sclerosis, result in nerve signals that cannot propagate to nerve endings, and as a consequence lead 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 response. Direct lineage conversion of mouse and rat fibroblasts into oligodendroglial cells provides a potential source of OPCs. Conversion by forced expression of both eight[163] or of the three[164] transcription factors Sox10, Olig2 and Zfp536, may provide such cells.


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[101] or microRNAs[14] to the heart.[165] 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.[101][166] These results implicated therapies that can directly remuscularize the heart without cell transplantation. However, the efficiency of such reprogramming turned out to be very low and the phenotype of received cardiomyocyte-like cells does not resemble those of a mature normal cardiomyocyte. Furthermore, transplantation of cardiac transcription factors into injured murine hearts resulted in poor cell survival and minimal expression of cardiac genes.[167]

Meanwhile, advances in the methods of obtaining cardiac myocytes in vitro occurred.[168][169] Efficient cardiac differentiation of human iPS cells gave rise to progenitors that were retained within infarcted rat hearts, and reduced remodeling of the heart after ischemic damage.[170]

Furthermore, ischemic cardiomyopathy in the murine infarction model was targeted by iPS cell transplantation. It synchronized failing ventricles, offering a regenerative strategy to achieve resynchronization and protection from decompensation by dint of improved left ventricular conduction and contractility, reduced scarring and reversal of structural remodelling.[171] One protocol generated populations of up to 98% cardiomyocytes from hPSCs simply by modulating the canonical Wnt signaling pathway at defined time points in during differentiation, using readily accessible small molecule compounds.[172]

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 intracellular TGF-β signaling. It thus selectively enhances the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells.[173]

One project seeded decellularized mouse hearts with human iPSC-derived multipotential cardiovascular progenitor cells. The introduced cells migrated, proliferated and differentiated in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the hearts. In addition, the heart's extracellular matrix (the substrate of heart scaffold) signalled the human 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.[174]

See also: review[175]

Rejuvenation of the muscle stem cell

The elderly often suffer from progressive muscle weakness and regenerative failure owing in part to elevated activity of the p38α and p38β mitogen-activated kinase pathway in senescent skeletal muscle stem cells. Subjecting such stem cells to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands and rejuvenates them that result in the return of their strength.[176]

In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions.[177]

Myogenic progenitors for potential use in disease modeling or cell-based therapies targeting skeletal muscle could also be generated directly from induced pluripotent stem cells using free-floating spherical culture (EZ spheres) in a culture medium supplemented with high concentrations (100 ng/ml) of fibroblast growth factor-2 (FGF-2) and epidermal growth factor.[178]


Unlike current protocols for deriving hepatocytes from human fibroblasts, Saiyong Zhu et al., (2014)[179] did not generate iPSCs but, using small molecules, cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) were efficiently differentiated. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of human primary adult hepatocytes. iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state.

An intestinal crypt - an accessible and abundant source of intestinal epithelial cells for conversion into β-like cells.

These results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.

Insulin-producing cells

Complications of Diabetes mellitus such as cardiovascular diseases, retinopathy, neuropathy, nephropathy, and peripheral circulatory diseases depend on sugar dysregulation due to lack of insulin from pancreatic beta cells and can be lethal if they are not treated. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs).[180] Unfortunately, human PSC-derived insulin-expressing cells resemble human fetal β cells rather than adult β cells. In contrast to adult β cells, fetal β cells seem functionally immature, as indicated by increased basal glucose secretion and lack of glucose stimulation and confirmed by RNA-seq of whose transcripts.[181]

Overexpression of the three transplantation.[183]

Nephron Progenitors

Adult proximal tubule cells were directly transcriptionally reprogrammed to [185]

Blood vessel cells

As blood vessels age, 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. Induced Vascular Progenitor Cells (iVPCs) are useful for cell-based therapy designed to stimulate coronary collateral growth. They were generated by partially reprogramming endothelial cells.[129] 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.[186]

Ex vivo genetic modification can be an effective strategy to enhance stem cell function. For example, cellular therapy employing genetic modification with Pim-1 kinase (a downstream effector of Akt, which positively regulates neovasculogenesis) of bone marrow–derived cells[187] or human cardiac progenitor cells, isolated from failing myocardium[188] results in durability of repair, together with the improvement of functional parameters of myocardial hemodynamic performance.

Stem cells extracted from fat tissue after liposuction may be coaxed into becoming progenitor smooth muscle cells (iPVSMCs) found in arteries and veins.[189]

The 2D culture system of human iPS cells[190] in conjunction with triple marker selection (CD34 (a surface glycophosphoprotein expressed on developmentally early embryonic fibroblasts), NP1 (receptor - neuropilin 1) and KDR (kinase insert domain-containing receptor)) for the isolation of vasculogenic precursor cells from human iPSC, generated endothelial cells that, after transplantation, formed stable, functional mouse blood vessels in vivo, lasting for 280 days.[191]

To treat infarction, it is important to prevent the formation of fibrotic scar tissue. This can be achieved in vivo by transient application of paracrine factors that redirect native heart progenitor stem cell contributions from scar tissue to cardiovascular tissue. For example, in a mouse myocardial infarction model, a single intramyocardial injection of human vascular endothelial growth factor A mRNA (VEGF-A modRNA), modified to escape the body's normal defense system, results in long-term improvement of heart function due to mobilization and redirection of epicardial progenitor cells toward cardiovascular cell types.[192]

Blood stem cells

Red blood cells

RBC transfusion is necessary for many patients. However, to date the supply of RBCs remains labile. In addition, transfusion risks infectious disease transmission. A large supply of safe RBCs generated in vitro would help to address this issue. Ex vivo erythroid cell generation may provide alternative transfusion products to meet present and future clinical requirements.[193][194] Red blood cells (RBC)s generated in vitro from mobilized CD34 positive cells have normal survival when transfused into an autologous recipient.[195] RBC produced in vitro contained exclusively fetal hemoglobin (HbF), which rescues the functionality of these RBCs. In vivo the switch of fetal to adult hemoglobin was observed after infusion of nucleated erythroid precursors derived from iPSCs.[196] Although RBCs do not have nuclei and therefore can not form a tumor, their immediate erythroblasts precursors have nuclei. 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.[197] Cell reprogramming often disrupts enucleation. Transfusion of in vitro-generated RBCs or erythroblasts does not sufficiently protect against tumor formation.

The aryl hydrocarbon receptor (AhR) pathway (which has been shown to be involved in the promotion of cancer cell development) plays an important role in normal blood cell development. AhR activation in human hematopoietic progenitor cells (HPs) drives an unprecedented expansion of HPs, megakaryocyte- and erythroid-lineage cells.[198] See also Concise Review:[199][200]


Platelets help prevent 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 clinical value. An RNA interference-based mechanism used a lentiviral vector to express short-hairpin RNAi targeting β2-microglobulin transcripts in CD34-positive cells. Generated platelets demonstrated an 85% reduction in class I HLA antigens. These platelets appeared to have normal function in vitro[201]

One clinically-applicable strategy for the derivation of functional platelets from human iPSC involves the establishment of stable immortalized megakaryocyte progenitor cell lines (imMKCLs) through 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.[202]

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 as a therapeutic strategy for combating many cancers and viral infections.[203] However, cell sources 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 coax them to redifferentiate back into T cells.[204][205][206]

Another method combines iPSC and chimeric antigen receptor (CAR) [207] technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture.[208] This approach of generating therapeutic human T cells may be useful for cancer immunotherapy and other medical applications.

Invariant natural killer T (iNKT) cells have great clinical potential as adjuvants 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).[209] The approach of collection, reprogramming/dedifferentiation, re-differentiation and injection has been proposed for related tumor treatment.[210]

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. DC-like antigen-presenting cells obtained from human induced pluripotent stem cells can serve as a source for vaccination therapy.[211]

CCAAT/enhancer binding protein-α (C/EBPα) induces transdifferentiation of B cells into macrophages at high efficiencies[212] and enhances reprogramming into iPS cells when co-expressed with transcription factors Oct4, Sox2, Klf4 and Myc.[213] with a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population.[214] Furthermore, C/EBPa can convert selected human B cell lymphoma and leukemia cell lines into macrophage-like cells at high efficiencies, impairing the cells’ tumor-forming capacity.[215]

Thymic epithelial cells rejuvenation

The FOXN1 has been implicated as a component of the mechanism regulating age-related involution.[216][217]

Clare Blackburn and colleagues show that established age-related thymic involution can be reversed by forced upregulation of just one transcription factor - FOXN1 in the thymic epithelial cells in order to promote rejuvenation, proliferation and differentiation of these cells into fully functional thymic epithelium.[218] This rejuvenation and increased proliferation was accompanied by upregulation of genes that promote cell cycle progression (cyclin D1, ΔNp63, FgfR2IIIb) and that are required in the thymic epithelial cells to promote specific aspects of T cell development (Dll4, Kitl, Ccl25, Cxcl12, Cd40, Cd80, Ctsl, Pax1).

Mesenchymal stem cells


mesenchymal stem/stromal cells (MSCs) are under investigation for applications in cardiac, renal, neural, joint and bone repair, as well as in inflammatory conditions and hemopoietic cotransplantation.[219] This is because of their immunosuppressive properties and ability to differentiate into a wide range of mesenchymal-lineage tissues. MSCs are typically harvested from adult bone marrow or fat, but these require painful invasive procedures and are low-frequency sources, making up only 0.001%– 0.01% of bone marrow cells and 0.05% in liposuction aspirates.[220] Of concern for autologous use, in particular in the elderly most in need of tissue repair, MSCs decline in quantity and quality with age.[219][221][222]

IPSCs could be obtained by the cells rejuvenation of even centenarians.[9][37] Because iPSCs can be harvested free of ethical constraints and culture can be expanded indefinitely, they are an advantageous source of MSCs.[223] IPSC treatment with SB-431542 leads to rapid and uniform MSC generation from human iPSCs. (SB-431542 is an inhibitor of activin/TGF- pathways by blocking phosphorylation of ALK4, ALK5, and ALK7 receptors.) These iPS-MSCs may lack teratoma-forming ability, display a normal stable karyotype in culture and exhibit growth and differentiation characteristics that closely resemble those of primary MSCs. It has potential for in vitro scale-up, enabling MSC-based therapies.[224] MSC derived from iPSC have the capacity to aid periodontal regeneration and are a promising source of readily accessible stem cells for use in the clinical treatment of periodontitis.[225][226]

Besides cell therapy in vivo, the culture of human mesenchymal stem cells can be used in vitro for mass-production of exosomes, which are ideal vehicles for drug delivery.[227]

Dedifferentiated adipocytes

Adipose tissue, because of its abundance and relatively less invasive harvest methods, represents a source of mesenchymal stem cells (MSCs). Unfortunately, liposuction aspirates are only 0.05% MSCs.[220] However, a large amount of mature adipocytes, which in general have lost their proliferative abilities and therefore are typically 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 express multipotent capacities.[228] Compared with adult stem cells, DFAT cells show unique advantages in abundance, isolation and homogeneity. Under proper induction culture in vitro or proper environment in vivo, DFAT cells could demonstrate adipogenic, osteogenic, chondrogenic, and myogenic potentials. They could also exhibit perivascular characteristics and elicit neovascularization.[229][230][231]

Chondrogenic 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 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 method of producing cartilage is to induce it from iPS cells.[232] Alternatively, it is possible to convert fibroblasts directly into induced chondrogenic cells (iChon) without an intermediate iPS cell stage, by inserting three reprogramming factors (c-MYC, KLF4, and SOX9).[233] Human iChon cells expressed marker genes for chondrocytes (type II collagen) but not fibroblasts.

Implanted into defects created in the articular cartilage of rats, human iChon cells survived to form cartilaginous tissue for at least four weeks, with no tumors. The method makes use of c-MYC, which is thought to have a major role in tumorigenesis and employs a retrovirus to introduce the reprogramming factors, excluding it from unmodified use in human therapy.[204][206][234]

Sources of cells for reprogramming

The most frequently used sources for reprogramming are blood cells[235][236][237][238] and fibroblasts, obtained by biopsy of the skin,[239] but taking cells from urine is less invasive.[240] The latter method does not require a biopsy or blood sampling. As of 2013, urine-derived stem cells had been differentiated into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic and neurogenic lineages, without forming teratomas.[241] Therefore, their epigenetic memory is suited to reprogramming into iPS cells. However, few cells appear in urine, only low conversion efficiencies had been achieved and the risk of bacterial contamination is relatively high.

Another promising source of cells for reprogramming are mesenchymal stem cells derived from human hair follicles.[242]

The origin of somatic cells used for reprogramming may influence the efficiency of reprogramming,[243][244] the functional properties of the resulting induced stem cells[245] and the ability to form tumors.[246]

IPSCs retain an epigenetic memory of their tissue of origin, which impacts their differentiation potential.[234][245][247][248][249][250] 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 during re-differentiation into specific cell types that require the specific loci bearing residual epigenetic marks.

See also


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
  • Takahashi, K.; Yamanaka, S. (2013). "Induced pluripotent stem cells in medicine and biology". Development 140 (12): 2457.  
  • 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. (2014) Cellular Reprogramming. Cold Spring Harb Perspect Biol. 6:a018606 doi:10.1101/cshperspect.a018606
  • 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
  • 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 [PDF]


  1. ^ Yamanaka, S.; Blau, H. M. (2010). "Nuclear reprogramming to a pluripotent state by three approaches". Nature 465 (7299): 704.  
  2. ^ Gurdon J. B. and Ian Wilmut (2011) Nuclear Transfer to Eggs and Oocytes Cold Spring Harb Perspect Biol; 3: a002659
  3. ^ a b c d Tachibana, M.; Amato, P.; Sparman, M.; Gutierrez, N. M.; Tippner-Hedges, R.; Ma, H.; Kang, E.; Fulati, A.; Lee, H. S.; Sritanaudomchai, H.; Masterson, K.; Larson, J.; Eaton, D.; Sadler-Fredd, K.; Battaglia, D.; Lee, D.; Wu, D.; Jensen, J.; Patton, P.; Gokhale, S.; Stouffer, R. L.; Wolf, D.; Mitalipov, S. (2013). "Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer". Cell 153 (6): 1228.  
  4. ^ Noggle, S.; Fung, H. L.; Gore, A.; Martinez, H.; Satriani, K. C.; Prosser, R.; Oum, K.; Paull, D.; Druckenmiller, S.; Freeby, M.; Greenberg, E.; Zhang, K.; Goland, R.; Sauer, M. V.; Leibel, R. L.; Egli, D. (2011). "Human oocytes reprogram somatic cells to a pluripotent state". Nature 478 (7367): 70.  
  5. ^ a b Pan, G.; Wang, T.; Yao, H.; Pei, D. (2012). "Somatic cell reprogramming for regenerative medicine: SCNT vs. IPS cells". BioEssays 34 (6): 472.  
  6. ^ Do, J. T.; Han, D. W.; Gentile, L; Sobek-Klocke, I; Stehling, M; Lee, H. T.; Schöler, H. R. (2007). "Erasure of cellular memory by fusion with pluripotent cells". Stem Cells 25 (4): 1013–20.  
  7. ^ a b Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.;  
  8. ^ Wang, W.; Yang, J.; Liu, H.; Lu, D.; Chen, X.; Zenonos, Z.; Campos, L. S.; Rad, R.; Guo, G.; Zhang, S.; Bradley, A.; Liu, P. (2011). "Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1". Proceedings of the National Academy of Sciences 108 (45): 18283.  
  9. ^ a b c Lapasset, L.; Milhavet, O.; Prieur, A.; Besnard, E.; Babled, A.; Ait-Hamou, N.; Leschik, J.; Pellestor, F.; Ramirez, J. -M.; De Vos, J.; Lehmann, S.; Lemaitre, J. -M. (2011). "Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state". Genes & Development 25 (21): 2248.  
  10. ^ Zhou, H.; Wu, S.; Joo, J. Y.; Zhu, S.; Han, D. W.; Lin, T.; Trauger, S.; Bien, G.; Yao, S.; Zhu, Y.; Siuzdak, G.; Schöler, H. R.; Duan, L.; Ding, S. (2009). "Generation of Induced Pluripotent Stem Cells Using Recombinant Proteins". Cell Stem Cell 4 (5): 381–4.  
  11. ^ Li, Z.; Rana, T. M. (2012). "Current Protocols in Stem Cell Biology".  
  12. ^ Anokye-Danso, F.; Trivedi, C. M.; Juhr, D.; Gupta, M.; Cui, Z.; Tian, Y.; Zhang, Y.; Yang, W.; Gruber, P. J.; Epstein, J. A.; Morrisey, E. E. (2011). "Highly Efficient miRNA-Mediated Reprogramming of Mouse and Human Somatic Cells to Pluripotency". Cell Stem Cell 8 (4): 376.  
  13. ^ Miyoshi, N.; Ishii, H.; Nagano, H.; Haraguchi, N.; Dewi, D. L.; Kano, Y.; Nishikawa, S.; Tanemura, M.; Mimori, K.; Tanaka, F.; Saito, T.; Nishimura, J.; Takemasa, I.; Mizushima, T.; Ikeda, M.; Yamamoto, H.; Sekimoto, M.; Doki, Y.; Mori, M. (2011). "Reprogramming of Mouse and Human Cells to Pluripotency Using Mature MicroRNAs". Cell Stem Cell 8 (6): 633.  
  14. ^ a b Jayawardena, T. M.; Egemnazarov, B.; Finch, E. A.; Zhang, L.; Payne, J. A.; Pandya, K.; Zhang, Z.; Rosenberg, P.; Mirotsou, M.; Dzau, V. J. (2012). "MicroRNA-Mediated in Vitro and in Vivo Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes". Circulation Research 110 (11): 1465.  
  15. ^ Bao, X.; Zhu, X.; Liao, B.; Benda, C.; Zhuang, Q.; Pei, D.; Qin, B.; Esteban, M. A. (2013). "MicroRNAs in somatic cell reprogramming". Current Opinion in Cell Biology 25 (2): 208.  
  16. ^ Yoshioka, N.; Gros, E.; Li, H. R.; Kumar, S.; Deacon, D. C.; Maron, C.; Muotri, A. R.; Chi, N. C.; Fu, X. D.; Yu, B. D.; Dowdy, S. F. (2013). "Efficient Generation of Human iPSCs by a Synthetic Self-Replicative RNA". Cell Stem Cell 13 (2): 246.  
  17. ^ a b Hou, P.; Li, Y.; Zhang, X.; Liu, C.; Guan, J.; Li, H.; Zhao, T.; Ye, J.; Yang, W.; Liu, K.; Ge, J.; Xu, J.; Zhang, Q.; Zhao, Y.; Deng, H. (2013). "Pluripotent Stem Cells Induced from Mouse Somatic Cells by Small-Molecule Compounds". Science 341 (6146): 651.  
    Efe, J. A.; Ding, S. (2011). "The evolving biology of small molecules: Controlling cell fate and identity". Philosophical Transactions of the Royal Society B: Biological Sciences 366 (1575): 2208.
  18. ^ a b Stadtfeld, M.; Apostolou, E.; Ferrari, F.; Choi, J.; Walsh, R. M.; Chen, T.; Ooi, S. S. K.; Kim, S. Y.; Bestor, T. H.; Shioda, T.; Park, P. J.; Hochedlinger, K. (2012). "Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all–iPS cell mice from terminally differentiated B cells". Nature Genetics 44 (4): 398.  
  19. ^ Pandian, G. N.; Sugiyama, H. (2012). "Programmable genetic switches to control transcriptional machinery of pluripotency". Biotechnology Journal 7 (6): 798.  
    Pandian, G. N.; Nakano, Y.; Sato, S.; Morinaga, H.; Bando, T.; Nagase, H.; Sugiyama, H. (2012). "A synthetic small molecule for rapid induction of multiple pluripotency genes in mouse embryonic fibroblasts". Scientific Reports 2: 544.
  20. ^ Box 3 FROM THE ARTICLE: Edward M. De Robertis (2006). Nature Reviews Molecular Cell Biology 7, 296-302 doi:10.1038/nrm1855
  21. ^ Slack, J. M. W. (2009). "Metaplasia and somatic cell reprogramming". The Journal of Pathology 217 (2): 161.  
  22. ^ Wei, G.; Schubiger, G.; Harder, F.; mÜller, A. M. (2000). "Stem Cell Plasticity in Mammals and Transdetermination in Drosophila: Common Themes?". Stem Cells 18 (6): 409.  
    Worley, M. I.; Setiawan, L.; Hariharan, I. K. (2012). "Regeneration and Transdetermination in Drosophila Imaginal Discs". Annual Review of Genetics 46: 289.
  23. ^ Peng-Fei Xu, Nathalie Houssin, Karine F. Ferri-Lagneau, Bernard Thisse and Christine Thisse. (April 2014). Construction of a Vertebrate Embryo from Two Opposing Morphogen Gradients. Science: 344(6179), 87-89 doi:10.1126/science.1248252
  24. ^ Stange, D. E.; Koo, B. K.; Huch, M.; Sibbel, G.; Basak, O.; Lyubimova, A.; Kujala, P.; Bartfeld, S.; Koster, J.; Geahlen, J. H.; Peters, P. J.; Van Es, J. H.; Van De Wetering, M.; Mills, J. C.; Clevers, H. (2013). "Differentiated Troy+ Chief Cells Act as Reserve Stem Cells to Generate All Lineages of the Stomach Epithelium". Cell 155 (2): 357.  
  25. ^ Tata, P. R.; Mou, H.; Pardo-Saganta, A.; Zhao, R.; Prabhu, M.; Law, B. M.; Vinarsky, V.; Cho, J. L.; Breton, S.; Sahay, A.; Medoff, B. D.; Rajagopal, J. (2013). "Dedifferentiation of committed epithelial cells into stem cells in vivo". Nature.  
  26. ^ Kusaba, T.; Lalli, M.; Kramann, R.; Kobayashi, A.; Humphreys, B. D. (2013). "Differentiated kidney epithelial cells repair injured proximal tubule". Proceedings of the National Academy of Sciences 111 (4): 1527.  
  27. ^ Sieweke, Michael H., Judith E. Allen (2013) Beyond Stem Cells: Self-Renewal of Differentiated Macrophages. Science : 342(6161) doi:10.1126/science.1242974 PMID 24264994
  28. ^ Sandoval-Guzmán, T.; Wang, H.; Khattak, S.; Schuez, M.; Roensch, K.; Nacu, E.; Tazaki, A.; Joven, A.; Tanaka, E. M.; Simon, A. S. (2014). "Fundamental Differences in Dedifferentiation and Stem Cell Recruitment during Skeletal Muscle Regeneration in Two Salamander Species". Cell Stem Cell 14 (2): 174.  
  29. ^ Kuroda Y, Wakao S, Kitada M, Murakami T, Nojima M, Dezawa M. (2013). Isolation, culture and evaluation of multilineage-differentiating stress-enduring (Muse) cells. Nat Protoc.;8(7):1391-415. doi:10.1038/nprot.2013.076
  30. ^ Kuroda, Y., Kitada, M., Wakao, S., et al. & Dezawa, M. (2010) Unique multipotent cells in adult human mesenchymal cell populations. PNAS , 107(19), 8639-8643. doi:10.1073/pnas.0911647107
  31. ^ Ogura F, Wakao S, Kuroda Y, Tsuchiyama K, Bagheri M, Heneidi S, Chazenbalk G, Aiba S, Dezawa M. (2014). Human Adipose Tissue Possesses a Unique Population of Pluripotent Stem Cells with Nontumorigenic and Low Telomerase Activities: Potential Implications in Regenerative Medicine. Stem Cells Dev. Epub ahead of print
  32. ^ Heneidi S, Simerman AA, Keller E, Singh P, Li X, et al. (2013). Awakened by Cellular Stress: Isolation and Characterization of a Novel Population of Pluripotent Stem Cells Derived from Human Adipose Tissue. PLoS ONE 8(6): e64752. doi:10.1371/journal.pone.0064752
  33. ^ Shigemoto T, Kuroda Y, Wakao S, Dezawa M (2013). A Novel Approach to Collecting Satellite Cells From Adult Skeletal Muscles on the Basis of Their Stress Tolerance. Stem Cells Trans Med 2 (7) 488-498 doi:10.5966/sctm.2012-0130
  34. ^ Sisakhtnezhad, S.; Matin, M. M. (2012). "Transdifferentiation: A cell and molecular reprogramming process". Cell and Tissue Research 348 (3): 379.  
  35. ^ Dinnyes, Andras; Tian, Xiuchun Cindy; Oback, Bj¨orn (17 April 2013). "Nuclear Transfer for Cloning Animals.". In Robert A. Meyers. Stem Cells: From Biology to Therapy. John Wiley & Sons. pp. 299–344.  
    Jullien, J.; Pasque, V.; Halley-Stott, R. P.; Miyamoto, K.; Gurdon, J. B. (2011). "Mechanisms of nuclear reprogramming by eggs and oocytes: A deterministic process?". Nature Reviews Molecular Cell Biology 12 (7): 453.

    Campbell, K. H. S. (2002). "A background to nuclear transfer and its applications in agriculture and human therapeutic medicine". Journal of Anatomy 200 (3): 267.
  36. ^ US 8,647,872  patent
  37. ^ a b Chung, Y. G.; Eum, J. H.; Lee, J. E.; Shim, S. H.; Sepilian, V.; Hong, S. W.; Lee, Y.; Treff, N. R.; Choi, Y. H.; Kimbrel, E. A.; Dittman, R. E.; Lanza, R.; Lee, D. R. (2014). "Human Somatic Cell Nuclear Transfer Using Adult Cells". Cell Stem Cell.
  38. ^ Yang, H.; Shi, L.; Wang, B. A.; Liang, D.; Zhong, C.; Liu, W.; Nie, Y.; Liu, J.; Zhao, J.; Gao, X.; Li, D.; Xu, G. L.; Li, J. (2012). "Generation of Genetically Modified Mice by Oocyte Injection of Androgenetic Haploid Embryonic Stem Cells". Cell 149 (3): 605.  
  39. ^ Hayashi, K.; Ogushi, S.; Kurimoto, K.; Shimamoto, S.; Ohta, H.; Saitou, M. (2012). "Offspring from Oocytes Derived from in Vitro Primordial Germ Cell-like Cells in Mice". Science 338 (6109): 971–975.  
  40. ^ Kishigami, S.; Mizutani, E.; Ohta, H.; Hikichi, T.; Thuan, N. V.; Wakayama, S.; Bui, H. T.; Wakayama, T. (2006). "Significant improvement of mouse cloning technique by treatment with trichostatin a after somatic nuclear transfer". Biochemical and Biophysical Research Communications 340: 183.  
  41. ^ Wakayama, S.; Kohda, T.; Obokata, H.; Tokoro, M.; Li, C.; Terashita, Y.; Mizutani, E.; Nguyen, V. T.; Kishigami, S.; Ishino, F.; Wakayama, T. (2013). "Successful Serial Recloning in the Mouse over Multiple Generations". Cell Stem Cell 12 (3): 293.  
  42. ^ Official website of the Presidential Commission for the Study of Bioethical Issues
  43. ^ Paull, D.; Emmanuele, V.; Weiss, K. A.; Treff, N.; Stewart, L.; Hua, H.; Zimmer, M.; Kahler, D. J.; Goland, R. S.; Noggle, S. A.; Prosser, R.; Hirano, M.; Sauer, M. V.; Egli, D. (2012). "Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants". Nature 493 (7434): 632.  
  44. ^ Tachibana, M.; Amato, P.; Sparman, M.; Woodward, J.; Sanchis, D. M.; Ma, H.; Gutierrez, N. M.; Tippner-Hedges, R.; Kang, E.; Lee, H. S.; Ramsey, C.; Masterson, K.; Battaglia, D.; Lee, D.; Wu, D.; Jensen, J.; Patton, P.; Gokhale, S.; Stouffer, R.; Mitalipov, S. (2012). "Towards germline gene therapy of inherited mitochondrial diseases". Nature 493 (7434): 627.  
  45. ^ Check Hayden, E. (2013). "Regulators weigh benefits of 'three-parent' fertilization". Nature 502 (7471): 284.  
  46. ^ Le, R.; Kou, Z.; Jiang, Y.; Li, M.; Huang, B.; Liu, W.; Li, H.; Kou, X.; He, W.; Rudolph, K. L.; Ju, Z.; Gao, S. (2014). "Enhanced Telomere Rejuvenation in Pluripotent Cells Reprogrammed via Nuclear Transfer Relative to Induced Pluripotent Stem Cells". Cell Stem Cell 14: 27.  
  47. ^ Cibelli, Jose; Lanza, Robert; Campbell, Keith H.S.; West, Michael D. (14 September 2002). Principles of Cloning. Academic Press.  
  48. ^ Shinagawa, T.; Takagi, T.; Tsukamoto, D.; Tomaru, C.; Huynh, L. M.; Sivaraman, P.; Kumarevel, T.; Inoue, K.; Nakato, R.; Katou, Y.; Sado, T.; Takahashi, S.; Ogura, A.; Shirahige, K.; Ishii, S. (2014). "Histone Variants Enriched in Oocytes Enhance Reprogramming to Induced Pluripotent Stem Cells". Cell Stem Cell 14 (2): 217.  
  49. ^ a b Abad, M. A.; Mosteiro, L.; Pantoja, C.; Cañamero, M.; Rayon, T.; Ors, I.; Graña, O.; Megías, D.; Domínguez, O.; Martínez, D.; Manzanares, M.; Ortega, S.; Serrano, M. (2013). "Reprogramming in vivo produces teratomas and iPS cells with totipotency features". Nature 502 (7471): 340.  
    Naik, Gautam (2013-09-11). "New Promise for Stem Cells -". Retrieved 2014-01-30. 
  50. ^ Stevens, L. C. (1970). "The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos". Developmental biology 21 (3): 364–82.  
  51. ^ Mintz, B; Cronmiller, C; Custer, R. P. (1978). "Somatic cell origin of teratocarcinomas". Proceedings of the National Academy of Sciences of the United States of America 75 (6): 2834–8.  
  52. ^ Mintz B, Illmensee K. (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci U S A; 72 (9) :3585-3589
  53. ^ MARTIN, G. R. & EVANS, M. J. (1975). Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc. Natn. Acad. Sci. U.S.A. 72, 1441-1445
  54. ^ Illmensee, K; Mintz, B (1976). "Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts". Proceedings of the National Academy of Sciences of the United States of America 73 (2): 549–53.  
  55. ^ Martin, GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. USA 78, 7634-7638
  56. ^ Martin, G. R. (1980). "Teratocarcinomas and mammalian embryogenesis". Science 209 (4458): 768–76.  
  57. ^ Papaioannou, V. E.; Gardner, R. L.; McBurney, M. W.; Babinet, C; Evans, M. J. (1978). "Participation of cultured teratocarcinoma cells in mouse embryogenesis". Journal of embryology and experimental morphology 44: 93–104.  
  58. ^ GRAHAM, C. F. (January 1977). "Teratocarcinoma cells and normal mouse embryogenesiseditor=Michael I. Sherman". Concepts in Mammalian Embryogenesis. MIT Press.  
  59. ^ ILLMENSEE, K. (14 June 2012). "Reversion of malignancy and normalized differentiation of teratocarcinoma cells in chimeric mice". In L. B. Russell. Genetic Mosaics and Chimeras in Mammals. Springer London, Limited. pp. 3–24.  
  60. ^ Stuart, H. T.; Van Oosten, A. L.; Radzisheuskaya, A.; Martello, G.; Miller, A.; Dietmann, S.; Nichols, J.; Silva, J.  C. R. (2014). "NANOG Amplifies STAT3 Activation and They Synergistically Induce the Naive Pluripotent Program". Current Biology 24 (3): 340.  
  61. ^ Boland, M. J.; Hazen, J. L.; Nazor, K. L.; Rodriguez, A. R.; Gifford, W; Martin, G; Kupriyanov, S; Baldwin, K. K. (2009). "Adult mice generated from induced pluripotent stem cells". Nature 461 (7260): 91–4.  
    Kang, L.; Wang, J.; Zhang, Y.; Kou, Z.; Gao, S. (2009). "IPS Cells Can Support Full-Term Development of Tetraploid Blastocyst-Complemented Embryos". Cell Stem Cell 5 (2): 135–8.
  62. ^ Yagi, T.; Kosakai, A.; Ito, D.; Okada, Y.; Akamatsu, W.; Nihei, Y.; Nabetani, A.; Ishikawa, F.; Arai, Y.; Hirose, N.; Okano, H.; Suzuki, N. (2012). "Establishment of Induced Pluripotent Stem Cells from Centenarians for Neurodegenerative Disease Research". PLoS ONE 7 (7): e41572.  
  63. ^ Rohani, L.; Johnson, A. A.; Arnold, A.; Stolzing, A. (2014). "The aging signature: A hallmark of induced pluripotent stem cells?". Aging Cell 13: 2.  
  64. ^ Yehezkel, S; Rebibo-Sabbah, A; Segev, Y; Tzukerman, M; Shaked, R; Huber, I; Gepstein, L; Skorecki, K; Selig, S (2011). "Reprogramming of telomeric regions during the generation of human induced pluripotent stem cells and subsequent differentiation into fibroblast-like derivatives". Epigenetics 6 (1): 63–75.  
  65. ^ West, M. D.; Vaziri, H (2010). "Back to immortality: The restoration of embryonic telomere length during induced pluripotency". Regenerative Medicine 5 (4): 485–8.  
  66. ^ Marión, R. M.; Blasco, M. A. (2010). "Telomere rejuvenation during nuclear reprogramming". Current Opinion in Genetics & Development 20 (2): 190–6.  
    Gourronc, F. A.; Klingelhutz, A. J. (2012). "Therapeutic opportunities: Telomere maintenance in inducible pluripotent stem cells". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 730 (1-2): 98–105.
  67. ^ Zhao, T.; Zhang, Z. N.; Rong, Z.; Xu, Y. (2011). "Immunogenicity of induced pluripotent stem cells". Nature 474 (7350): 212–5.  
  68. ^ Dhodapkar, M. V.; Dhodapkar, K. M. (2011). "Spontaneous and therapy-induced immunity to pluripotency genes in humans: Clinical implications, opportunities and challenges". Cancer Immunology, Immunotherapy 60 (3): 413–8.  
  69. ^ Gutierrez-Aranda, I.; Ramos-Mejia, V.; Bueno, C.; Munoz-Lopez, M.; Real, P. J.; Mácia, A.; Sanchez, L.; Ligero, G.; Garcia-Parez, J. L.; Menendez, P. (2010). "Human Induced Pluripotent Stem Cells Develop Teratoma More Efficiently and Faster Than Human Embryonic Stem Cells Regardless the Site of Injection". Stem Cells 28 (9): 1568–1570.  
  70. ^ Chang, C. J.; Mitra, K.; Koya, M.; Velho, M.; Desprat, R.; Lenz, J.; Bouhassira, E. E. (2011). "Production of Embryonic and Fetal-Like Red Blood Cells from Human Induced Pluripotent Stem Cells". PLoS ONE 6 (10): e25761.  
  71. ^ a b Dabir, D. V.; Hasson, S. A.; Setoguchi, K.; Johnson, M. E.; Wongkongkathep, P.; Douglas, C. J.; Zimmerman, J.; Damoiseaux, R.; Teitell, M. A.; Koehler, C. M. (2013). "A Small Molecule Inhibitor of Redox-Regulated Protein Translocation into Mitochondria". Developmental Cell 25: 81.  
  72. ^ Uri Ben-David, Qing-Fen Gan, Tamar Golan-Lev, et al & Nissim Benvenisty (2013) Selective Elimination of Human Pluripotent Stem Cells by an Oleate Synthesis Inhibitor Discovered in a High-Throughput Screen Cell Stem Cell, 12(2), 167-179
    Lou, K. J. (2013). "Small molecules vs. Teratomas". Science-Business eXchange 6 (7).  
  73. ^ Lee, M. -O.; Moon, S. H.; Jeong, H. -C.; Yi, J. -Y.; Lee, T. -H.; Shim, S. H.; Rhee, Y. -H.; Lee, S. -H.; Oh, S. -J.; Lee, M. -Y.; Han, M. -J.; Cho, Y. S.; Chung, H. -M.; Kim, K. -S.; Cha, H. -J. (2013). "Inhibition of pluripotent stem cell-derived teratoma formation by small molecules". Proceedings of the National Academy of Sciences 110 (35): E3281.  
  74. ^ Tang, C; Weissman, I. L.; Drukker, M (2012). "The safety of embryonic stem cell therapy relies on teratoma removal". Oncotarget 3 (1): 7–8.  
  75. ^ Chaffer, C. L.; Brueckmann, I.; Scheel, C.; Kaestli, A. J.; Wiggins, P. A.; Rodrigues, L. O.; Brooks, M.; Reinhardt, F.; Su, Y.; Polyak, K.; Arendt, L. M.; Kuperwasser, C.; Bierie, B.; Weinberg, R. A. (2011). "Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state". Proceedings of the National Academy of Sciences 108 (19): 7950.  
  76. ^ Gurtan, A. M.; Ravi, A.; Rahl, P. B.; Bosson, A. D.; Jnbaptiste, C. K.; Bhutkar, A.; Whittaker, C. A.; Young, R. A.; Sharp, P. A. (2013). "Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts". Genes & Development 27 (8): 941.  
    Wang, H.; Wang, X.; Xu, X.; Zwaka, T. P.; Cooney, A. J. (2013). "Epigenetic Reprogramming of the Germ Cell Nuclear Factor Gene is Required for Proper Differentiation of Induced Pluripotent Cells". Stem Cells 31 (12): 2659.
  77. ^ Lindgren, A. G.; Natsuhara, K.; Tian, E.; Vincent, J. J.; Li, X.; Jiao, J.; Wu, H.; Banerjee, U.; Clark, A. T. (2011). "Loss of Pten Causes Tumor Initiation Following Differentiation of Murine Pluripotent Stem Cells Due to Failed Repression of Nanog". PLoS ONE 6: e16478.  
  78. ^ Grad, I; Hibaoui, Y; Jaconi, M; Chicha, L; Bergström-Tengzelius, R; Sailani, M. R.; Pelte, M. F.; Dahoun, S; Mitsiadis, T. A.; Töhönen, V; Bouillaguet, S; Antonarakis, S. E.; Kere, J; Zucchelli, M; Hovatta, O; Feki, A (2011). "NANOG priming before full reprogramming may generate germ cell tumours". European cells & materials 22: 258–74; discussio 274.  
  79. ^ Okano, H.; Nakamura, M.; Yoshida, K.; Okada, Y.; Tsuji, O.; Nori, S.; Ikeda, E.; Yamanaka, S.; Miura, K. (2013). "Steps Toward Safe Cell Therapy Using Induced Pluripotent Stem Cells". Circulation Research 112 (3): 523.  
    Cunningham, J. J.; Ulbright, T. M.; Pera, M. F.; Looijenga, L. H. J. (2012). "Lessons from human teratomas to guide development of safe stem cell therapies". Nature Biotechnology 30 (9): 849.
  80. ^ Bellin, M.; Marchetto, M. C.; Gage, F. H.; Mummery, C. L. (2012). "Induced pluripotent stem cells: The new patient?". Nature Reviews Molecular Cell Biology 13 (11): 713.  
    Sandoe, J.; Eggan, K. (2013). "Opportunities and challenges of pluripotent stem cell neurodegenerative disease models". Nature Neuroscience 16 (7): 780.
  81. ^ Takahashi, K.; Yamanaka, S. (2013). "Induced pluripotent stem cells in medicine and biology". Development 140 (12): 2457.  
    Fu, X; Xu, Y (2012). "Challenges to the clinical application of pluripotent stem cells: Towards genomic and functional stability". Genome Medicine 4 (6): 55.
  82. ^ Araki, R.; Uda, M.; Hoki, Y.; Sunayama, M.; Nakamura, M.; Ando, S.; Sugiura, M.; Ideno, H.; Shimada, A.; Nifuji, A.; Abe, M. (2013). "Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells". Nature 494 (7435): 100.  
    Wahlestedt, M.; Norddahl, G. L.; Sten, G.; Ugale, A.; Frisk, M. -A. M.; Mattsson, R.; Deierborg, T.; Sigvardsson, M.; Bryder, D. (2013). "An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state". Blood 121 (21): 4257.
  83. ^ Ohnishi, K., Semi, K., Yamamoto, T., Shimizu, M., Tanaka, A., Mitsunaga, K., ... & Yamada, Y. (2014). Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation. Cell, 156(4), 663-677. doi:10.1016/j.cell.2014.01.005
  84. ^ Mfopou JK, De Groote V, Xu X, Heimberg H, Bouwens L (May 2007). "Sonic hedgehog and other soluble factors from differentiating embryoid bodies inhibit pancreas development". Stem Cells 25 (5): 1156–65.  
  85. ^ De Los Angeles, A., & Daley, G. Q. (2013) A chemical logic for reprogramming to pluripotency doi:10.1038/cr.2013.119
    Federation, A. J., Bradner, J. E., & Meissner, A. (2013) The use of small molecules in somatic-cell reprogramming. Trends in cell biology. doi:10.1016/j.tcb.2013.09.011
  87. ^ Amabile, G.; Welner, R. S.; Nombela-Arrieta, C.; d'Alise, A. M.; Di Ruscio, A.; Ebralidze, A. K.; Kraytsberg, Y.; Ye, M.; Kocher, O.; Neuberg, D. S.; Khrapko, K.; Silberstein, L. E.; Tenen, D. G. (2012). "In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells". Blood 121 (8): 1255.  
  88. ^ Suzuki, N.; Yamazaki, S.; Yamaguchi, T.; Okabe, M.; Masaki, H.; Takaki, S.; Otsu, M.; Nakauchi, H. (2013). "Generation of Engraftable Hematopoietic Stem Cells from Induced Pluripotent Stem Cells by Way of Teratoma Formation". Molecular Therapy 21 (7): 1424.  
  89. ^ Chou, B. K.; Ye, Z.; Cheng, L. (2013). "Generation and Homing of iPSC-Derived Hematopoietic Cells in Vivo". Molecular Therapy 21 (7): 1292.  
  90. ^ Yamauchi, T; Takenaka, K; Urata, S; Shima, T; Kikushige, Y; Tokuyama, T; Iwamoto, C; Nishihara, M; Iwasaki, H; Miyamoto, T; Honma, N; Nakao, M; Matozaki, T; Akashi, K (2013). "Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment". Blood 121 (8): 1316–25.  
  91. ^ Rong, Z.; Wang, M.; Hu, Z.; Stradner, M.; Zhu, S.; Kong, H.; Yi, H.; Goldrath, A.; Yang, Y. G.; Xu, Y.; Fu, X. (2014). "An Effective Approach to Prevent Immune Rejection of Human ESC-Derived Allografts". Cell Stem Cell 14: 121.  
  92. ^ Hirami, Y.; Osakada, F.; Takahashi, K.; Okita, K.; Yamanaka, S.; Ikeda, H.; Yoshimura, N.; Takahashi, M. (2009). "Generation of retinal cells from mouse and human induced pluripotent stem cells". Neuroscience Letters 458 (3): 126.  
  93. ^ Buchholz, D. E.; Hikita, S. T.; Rowland, T. J.; Friedrich, A. M.; Hinman, C. R.; Johnson, L. V.; Clegg, D. O. (2009). "Derivation of Functional Retinal Pigmented Epithelium from Induced Pluripotent Stem Cells". Stem Cells 27 (10): 2427.  
  94. ^ Jin Yang, Eva Nong, Stephen H Tsang (2013) Induced pluripotent stem cells and retinal degeneration treatment. Expert Rev. Ophthalmol. 8(1), 5–8 doi: 10.1586/EOP.12.75
    Fields,, Mark A.; Hwang,, John; Gong,, Jie; Cai,, Hui; Del Priore, Lucian (9 December 2012). "The Eye as a Target Organ for Stem Cell Therapy". In Stephen Tsang. Stem Cell Biology and Regenerative Medicine in Ophthalmology. Springer. pp. 1–30.  
  95. ^ Li Y, Tsai YT, Hsu CW et al. (2012) Long-term safety and efficacy of human induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa Mol. Med. 18(1), 1312–1319 doi:10.2119/molmed.2012.00242
  96. ^ Stem cell therapy for RP is now offered at St. Luke’s Medical Center.
  97. ^ Tzouvelekis, A.; Ntolios, P.; Bouros, D. (2013). "Stem Cell Treatment for Chronic Lung Diseases". Respiration 85 (3): 179.  
  98. ^ Wagner, Darcy E.; Bonvillain, Ryan W.; Jensen, Todd; Girard, Eric D.; Bunnell, Bruce A.; Finck, Christine M.; Hoffman5, Andrew M.; Weiss2, Daniel J. (Jul 2013). "Can stem cells be used to generate new lungs? Ex vivo lung bioengineering with decellularized whole lung scaffolds". Respirology 18 (6): 895–911.  
  99. ^ Wong, A. P., & Rossant, J. (2013) Generation of Lung Epithelium from Pluripotent Stem Cells. Current pathobiology reports, 1(2), 137-145, DOI: 10.1007/s40139-013-0016-9
    Mou, H.; Zhao, R.; Sherwood, R.; Ahfeldt, T.; Lapey, A.; Wain, J.; Sicilian, L.; Izvolsky, K.; Lau, F. H.; Musunuru, K.; Cowan, C.; Rajagopal, J. (2012). "Generation of Multipotent Lung and Airway Progenitors from Mouse ESCs and Patient-Specific Cystic Fibrosis iPSCs". Cell Stem Cell 10 (4): 385.  
    Ghaedi, M.; Calle, E. A.; Mendez, J. J.; Gard, A. L.; Balestrini, J.; Booth, A.; Bove, P. F.; Gui, L.; White, E. S.; Niklason, L. E. (2013). "Human iPS cellâ€"derived alveolar epithelium repopulates lung extracellular matrix". Journal of Clinical Investigation 123 (11): 4950.

    Ghaedi, M.; Mendez, J. J.; Bove, P. F.; Sivarapatna, A.; Raredon, M. S. B.; Niklason, L. E. (2014). "Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor". Biomaterials 35 (2): 699.
    Huang, S. X. L.; Islam, M. N.; O'Neill, J.; Hu, Z.; Yang, Y. G.; Chen, Y. W.; Mumau, M.; Green, M. D.; Vunjak-Novakovic, G.; Bhattacharya, J.; Snoeck, H. W. (2013). "Efficient generation of lung and airway epithelial cells from human pluripotent stem cells". Nature Biotechnology 32: 84.
  100. ^ Niu, Z.; Hu, Y.; Chu, Z.; Yu, M.; Bai, Y.; Wang, L.; Hua, J. (2013). "Germ-like cell differentiation from induced pluripotent stem cells (iPSCs)". Cell Biochemistry and Function 31: 12.  
    Yang, S.; Bo, J.; Hu, H.; Guo, X.; Tian, R.; Sun, C.; Zhu, Y.; Li, P.; Liu, P.; Zou, S.; Huang, Y.; Li, Z. (2012). "Derivation of male germ cells from induced pluripotent stem cells in vitro and in reconstituted seminiferous tubules". Cell Proliferation 45 (2): 91.

    Panula, S.; Medrano, J. V.; Kee, K.; Bergstrom, R.; Nguyen, H. N.; Byers, B.; Wilson, K. D.; Wu, J. C.; Simon, C.; Hovatta, O.; Reijo Pera, R. A. (2010). "Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells". Human Molecular Genetics 20 (4): 752.
  101. ^ a b c Qian, L.; Huang, Y.; Spencer, C. I.; Foley, A.; Vedantham, V.; Liu, L.; Conway, S. J.; Fu, J. D.; Srivastava, D. (2012). "In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes". Nature 485 (7400): 593.  
  102. ^ Szabo, E.; Rampalli, S.; Risueño, R. M.; Schnerch, A.; Mitchell, R.; Fiebig-Comyn, A.; Levadoux-Martin, M.; Bhatia, M. (2010). "Direct conversion of human fibroblasts to multilineage blood progenitors". Nature 468 (7323): 521–526.  
  103. ^ Efe, J. A.; Hilcove, S.; Kim, J.; Zhou, H.; Ouyang, K.; Wang, G.; Chen, J.; Ding, S. (2011). "Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy". Nature Cell Biology 13 (3): 215–222.  
  104. ^ a b Lujan, E.; Chanda, S.; Ahlenius, H.; Sudhof, T. C.; Wernig, M. (2012). "Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells". Proceedings of the National Academy of Sciences 109 (7): 2527.  
  105. ^ a b Thier, M.; Wörsdörfer, P.; Lakes, Y. B.; Gorris, R.; Herms, S.; Opitz, T.; Seiferling, D.; Quandel, T.; Hoffmann, P.; Nöthen, M. M.; Brüstle, O.; Edenhofer, F. (2012). "Direct Conversion of Fibroblasts into Stably Expandable Neural Stem Cells". Cell Stem Cell 10 (4): 473.  
  106. ^ a b c Han, D. W.; Tapia, N.; Hermann, A.; Hemmer, K.; Höing, S.; Araúzo-Bravo, M. J.; Zaehres, H.; Wu, G.; Frank, S.; Moritz, S. R.; Greber, B.; Yang, J. H.; Lee, H. T.; Schwamborn, J. C.; Storch, A.; Schöler, H. R. (2012). "Direct Reprogramming of Fibroblasts into Neural Stem Cells by Defined Factors". Cell Stem Cell 10 (4): 465.  
  107. ^ Taylor, S. M.; Jones, P. A. (1979). "Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine". Cell 17 (4): 771–9.  
  108. ^ Lassar, A. B.; Paterson, B. M.; Weintraub, H (1986). "Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts". Cell 47 (5): 649–56.  
    Davis, R. L.; Weintraub, H.; Lassar, A. B. (1987). "Expression of a single transfected cDNA converts fibroblasts to myoblasts". Cell 51 (6): 987–1000.

    Weintraub, H; Tapscott, S. J.; Davis, R. L.; Thayer, M. J.; Adam, M. A.; Lassar, A. B.; Miller, A. D. (1989). "Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD". Proceedings of the National Academy of Sciences of the United States of America 86 (14): 5434–8.
  109. ^ Vierbuchen, T.; Wernig, M. (2011). "Direct lineage conversions: Unnatural but useful?". Nature Biotechnology 29 (10): 892.  
  110. ^ Riddle, M. R.; Weintraub, A.; Nguyen, K. C. Q.; Hall, D. H.; Rothman, J. H. (2013). "Transdifferentiation and remodeling of post-embryonic C. Elegans cells by a single transcription factor". Development 140 (24): 4844.  
  111. ^ Jung, D. W.; Williams, D. R. (2011). "Novel Chemically Defined Approach to Produce Multipotent Cells from Terminally Differentiated Tissue Syncytia". ACS Chemical Biology 6 (6): 553.  
    "In This Issue". ACS Chemical Biology 7 (4): 619. 2012.
  112. ^ Hongkai Zhang, Ian A. Wilson, and Richard A. Lerner (2012) Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries. PNAS. 109(39), 15728-15733 doi:10.1073/pnas.1214275109
  113. ^ Antibody that Transforms Bone Marrow Stem Cells Directly into Brain Cells
    Jia Xie, Hongkai Zhang, Kyungmoo Yea, and Richard A. Lerner (2013) Autocrine signaling based selection of combinatorial antibodies that transdifferentiate human stem cells PNAS; doi:10.1073/pnas.1306263110
  114. ^ a b c d Liu, X.; Ory, V.; Chapman, S.; Yuan, H.; Albanese, C.; Kallakury, B.; Timofeeva, O. A.; Nealon, C.; Dakic, A.; Simic, V.; Haddad, B. R.; Rhim, J. S.; Dritschilo, A.; Riegel, A.; McBride, A.; Schlegel, R. (2012). "ROCK Inhibitor and Feeder Cells Induce the Conditional Reprogramming of Epithelial Cells". The American Journal of Pathology 180 (2): 599.  
  115. ^ Rheinwald, J. G.; Green, H (1975). "Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells". Cell 6 (3): 331–43.  
  116. ^ Hiew, Y.-L. (2011) Examining the biological consequences of DNA damage caused by irradiated J2-3T3 fibroblast feeder cells and HPV16: characterisation of the biological functions of Mll. Doctoral thesis, UCL (University College London)
  117. ^ Szumiel, I. (2012). "Radiation hormesis: Autophagy and other cellular mechanisms". International Journal of Radiation Biology 88 (9): 619.  
  118. ^ Kurosawa, H. (2012). "Application of Rho-associated protein kinase (ROCK) inhibitor to human pluripotent stem cells". Journal of Bioscience and Bioengineering 114 (6): 577.  
  119. ^ Terunuma, A.; Limgala, R. P.; Park, C. J.; Choudhary, I.; Vogel, J. C. (2010). "Efficient Procurement of Epithelial Stem Cells from Human Tissue Specimens Using a Rho-Associated Protein Kinase Inhibitor Y-27632". Tissue Engineering Part A 16 (4): 1363.  
  120. ^ Sandra Chapman, Xuefeng Liu, Craig Meyers, Richard Schlegel, and Alison A. McBride. ( 2010) Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor
  121. ^ Suprynowicz, F. A.; Upadhyay, G.; Krawczyk, E.; Kramer, S. C.; Hebert, J. D.; Liu, X.; Yuan, H.; Cheluvaraju, C.; Clapp, P. W.; Boucher, R. C.; Kamonjoh, C. M.; Randell, S. H.; Schlegel, R. (2012). "Conditionally reprogrammed cells represent a stem-like state of adult epithelial cells". Proceedings of the National Academy of Sciences 109 (49): 20035.  
  122. ^ a b Agarwal, S.; Rimm, D. L. (2012). "Making Every Cell Like He La". The American Journal of Pathology 180 (2): 443.  
  123. ^ a b Lisanti MP, Tanowitz HB. (2012) Translational discoveries, personalized medicine, and living biobanks of the future. The American Journal of Pathology, 2012 Apr;180(4):1334-6
  124. ^ Yuan, H.; Myers, S.; Wang, J.; Zhou, D.; Woo, J. A.; Kallakury, B.; Ju, A.; Bazylewicz, M.; Carter, Y. M.; Albanese, C.; Grant, N.; Shad, A.; Dritschilo, A.; Liu, X.; Schlegel, R. (2012). "Use of Reprogrammed Cells to Identify Therapy for Respiratory Papillomatosis". New England Journal of Medicine 367 (13): 1220.  
  125. ^ Palechor-Ceron, N.; Suprynowicz, F. A.; Upadhyay, G.; Dakic, A.; Minas, T.; Simic, V.; Johnson, M.; Albanese, C.; Schlegel, R.; Liu, X. (2013). "Radiation Induces Diffusible Feeder Cell Factor(s) That Cooperate with ROCK Inhibitor to Conditionally Reprogram and Immortalize Epithelial Cells". The American Journal of Pathology 183 (6): 1862.  
  126. ^
  127. ^ Sukhbir Kaur, David R. Soto-Pantoja, Erica V. Stein et al. & David D. Roberts. ( 2013) Thrombospondin-1 Signaling through CD47 Inhibits Self-renewal by Regulating c-Myc and Other Stem Cell Transcription Factors. Scientific Reports; 3, Article number: 1673 doi:10.1038/srep01673
  128. ^ Soto-Pantoja, D. R.; Ridnour, L. A.; Wink, D. A.; Roberts, D. D. (2013). "Blockade of CD47 increases survival of mice exposed to lethal total body irradiation". Scientific Reports 3.  
  129. ^ a b Leo Kurian, Ignacio Sancho-Martinez, Emmanuel Nivet, et al. & Juan Carlos Izpisua Belmonte (2012) Conversion of human fibroblasts to angioblast-like progenitor cells. Nature Methods. doi:10.1038/nmeth.2255
  130. ^ Morris, S. A., & Daley, G. Q. (2013). A blueprint for engineering cell fate: current technologies to reprogram cell identity. Cell research, 23(1), 33-48. doi:10.1038/cr.2013.1
  131. ^ Wang, Y. C.; Nakagawa, M.; Garitaonandia, I.; Slavin, I.; Altun, G.; Lacharite, R. M.; Nazor, K. L.; Tran, H. T.; Lynch, C. L.; Leonardo, T. R.; Liu, Y.; Peterson, S. E.; Laurent, L. C.; Yamanaka, S.; Loring, J. F. (2011). "Specific lectin biomarkers for isolation of human pluripotent stem cells identified through array-based glycomic analysis". Cell Research 21 (11): 1551.  
  132. ^ Thomson, J. A.; Itskovitz-Eldor, J; Shapiro, S. S.; Waknitz, M. A.; Swiergiel, J. J.; Marshall, V. S.; Jones, J. M. (1998). "Embryonic Stem Cell Lines Derived from Human Blastocysts". Science 282 (5391): 1145–7.  
  133. ^ Suila, H.; Hirvonen, T.; Ritamo, I.; Natunen, S.; Tuimala, J.; Laitinen, S.; Anderson, H.; Nystedt, J.; Räbinä, J.; Valmu, L. (2014). "Extracellular O-Linked N-Acetylglucosamine is Enriched in Stem Cells Derived from Human Umbilical Cord Blood". BioResearch Open Access 3 (2): 39.  
  134. ^ Perdigoto, C. N., & Bardin, A. J. (2013). Sending the right signal: Notch and stem cells. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(2), 2307-2322.
  135. ^ Jafar-Nejad, H., Leonardi, J., & Fernandez-Valdivia, R. (2010). Role of glycans and glycosyltransferases in the regulation of Notch signaling. Glycobiology, 20(8), 931-949. doi:10.1093/glycob/cwq053
  136. ^ Frederico Alisson-Silva, Deivid de Carvalho Rodrigues, Leandro Vairo, et al. and Adriane R Todeschini (2014). Evidences for the involvement of cell surface glycans in stem cell pluripotency and differentiation. Glycobiology 24 (5): 458-468. doi:10.1093/glycob/cwu012
  137. ^ Hasehira, K.; Tateno, H.; Onuma, Y.; Ito, Y.; Asashima, M.; Hirabayashi, J. (2012). "Structural and Quantitative Evidence for Dynamic Glycome Shift on Production of Induced Pluripotent Stem Cells". Molecular & Cellular Proteomics 11 (12): 1913.  
  138. ^ Becker Kojic', Z. A. (2002). "A Novel Human Erythrocyte Glycosylphosphatidylinositol (GPI)-anchored Glycoprotein ACA. ISOLATION, PURIFICATION, PRIMARY STRUCTURE DETERMINATION, AND MOLECULAR PARAMETERS OF ITS LIPID STRUCTURE". Journal of Biological Chemistry 277 (43): 40472.  
  139. ^ Becker-Kojić, Z. A.; Ureña-Peralta, J. R.; Saffrich, R; Rodriguez-Jiménez, F. J.; Rubio, M. P.; Rios, P; Romero, A; Ho, A. D.; Stojković, M (2013). "A novel human glycoprotein ACA is an upstream regulator of human hematopoiesis". Bulletin of experimental biology and medicine 155 (4): 536–51.  
  140. ^ ZABecker-Kojič, JRUreña-Peralta, I.Zipančić, et al. & M.Stojkovič ( 2013 ) Activation of surface glycoprotein ACA induced pluripotent hematopoietic progenitor cells. CELL TECHNOLOGIES IN BIOLOGY AND MEDICINE , 9 (2 ) , 85-101
  141. ^ Mikkola, M. (2013) Human pluripotent stem cells: glycomic approaches for culturing and characterization.ISBN 978-952-10-8444-7
  142. ^ Redmer, T.; Diecke, S.; Grigoryan, T.; Quiroga-Negreira, A.; Birchmeier, W.; Besser, D. (2011). "E-cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming". EMBO reports 12 (7): 720.  
  143. ^ Bedzhov, I.; Alotaibi, H.; Basilicata, M. F.; Ahlborn, K.; Liszewska, E.; Brabletz, T.; Stemmler, M. P. (2013). "Adhesion, but not a specific cadherin code, is indispensable for ES cell and induced pluripotency". Stem Cell Research 11 (3): 1250.  
  144. ^ Su, G.; Zhao, Y.; Wei, J.; Xiao, Z.; Chen, B.; Han, J.; Chen, L.; Guan, J.; Wang, R.; Dong, Q.; Dai, J. (2013). "Direct conversion of fibroblasts into neural progenitor-like cells by forced growth into 3D spheres on low attachment surfaces". Biomaterials 34 (24): 5897.  
  145. ^ Downing, T. L.; Soto, J.; Morez, C.; Houssin, T.; Fritz, A.; Yuan, F.; Chu, J.; Patel, S.; Schaffer, D. V.; Li, S. (2013). "Biophysical regulation of epigenetic state and cell reprogramming". Nature Materials 12 (12): 1154.  
  146. ^ Yubing Sun, Koh Meng Aw Yong, Luis G. Villa-Diaz, et al. & Jianping Fu(2014). Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cells. Nature Materials doi:10.1038/nmat3945
  147. ^ Murray, P.; Prewitz, M.; Hopp, I.; Wells, N.; Zhang, H.; Cooper, A.; Parry, K. L.; Short, R.; Antoine, D. J.; Edgar, D. (2013). "The self-renewal of mouse embryonic stem cells is regulated by cell–substratum adhesion and cell spreading". The International Journal of Biochemistry & Cell Biology 45 (11): 2698.  
  148. ^ Guilak, F., Cohen, D. M., Estes, B. T., et al. & Chen, C. S. (2009) Control of stem cell fate by physical interactions with the extracellular matrix. Cell stem cell, 5(1), 17-26. doi: 10.1016/j.stem.2009.06.016
    Worley, K.; Certo, A.; Wan, L. Q. (2012). "Geometry–Force Control of Stem Cell Fate". BioNanoScience 3: 43.  
  149. ^ Singh, A.; Suri, S.; Lee, T.; Chilton, J. M.; Cooke, M. T.; Chen, W.; Fu, J.; Stice, S. L.; Lu, H.; McDevitt, T. C.; García, A. S. J. (2013). "Adhesion strength–based, label-free isolation of human pluripotent stem cells". Nature Methods 10 (5): 438.  
  150. ^ Wang, Kainan; Degerny, Cindy; Xu, Minghong; Yang, Xiang-Jiao (2009). YAP, TAZ, and Yorkie: A conserved family of signal-responsive transcriptional coregulators in animal development and human disease. Biochemistry and Cell Biology 87 (1): 77–91. doi:10.1139/O08-114
  151. ^ Yang C., Tibbitt M.W., Basta L. & Anseth K.S. (2014). Mechanical memory and dosing influence stem cell fate. Nature Materials, doi:10.1038/nmat3889
  152. ^ Nampe, D., & Tsutsui, H. (2013). Engineered Micromechanical Cues Affecting Human Pluripotent Stem Cell Regulations and Fate. Journal of laboratory automation, 18(6), 482-493. doi:10.1177/2211068213503156
  153. ^ Zhang, W.; Duan, S.; Li, Y.; Xu, X.; Qu, J.; Zhang, W.; Liu, G. H. (2012). "Converted neural cells: Induced to a cure?". Protein & Cell 3 (2): 91.  
  154. ^ Yang, N.; Ng, Y. H.; Pang, Z. P.; Südhof, T. C.; Wernig, M. (2011). "Induced Neuronal Cells: How to Make and Define a Neuron". Cell Stem Cell 9 (6): 517.  
  155. ^ Sheng, C.; Zheng, Q.; Wu, J.; Xu, Z.; Sang, L.; Wang, L.; Guo, C.; Zhu, W.; Tong, M.; Liu, L.; Li, W.; Liu, Z. H.; Zhao, X. Y.; Wang, L.; Chen, Z.; Zhou, Q. (2012). "Generation of dopaminergic neurons directly from mouse fibroblasts and fibroblast-derived neural progenitors". Cell Research 22 (4): 769.  
  156. ^ a b Maucksch, C., E. Firmin, et al. (2012). "Non-viral generation of neural precursor-like cells from adult human fibroblasts" J Stem Cells Regen Med 8(3): 1-9.
  157. ^ Ring, K. L.; Tong, L. M.; Balestra, M. E.; Javier, R.; Andrews-Zwilling, Y.; Li, G.; Walker, D.; Zhang, W. R.; Kreitzer, A. C.; Huang, Y. (2012). "Direct Reprogramming of Mouse and Human Fibroblasts into Multipotent Neural Stem Cells with a Single Factor". Cell Stem Cell 11: 100.  
  158. ^ a b Generation of neural progenitor cells by chemical cocktails and hypoxia Cheng, L.; Hu, W.; Qiu, B.; Zhao, J.; Yu, Y.; Guan, W.; Wang, M.; Yang, W.; Pei, G. (2014). "Generation of neural progenitor cells by chemical cocktails and hypoxia". Cell Research.  
  159. ^ Liu, G. H.; Yi, F.; Suzuki, K.; Qu, J.; Belmonte, J. C. I. (2012). "Induced neural stem cells: A new tool for studying neural development and neurological disorders". Cell Research 22 (7): 1087.  
  160. ^ Torper, O.; Pfisterer, U.; Wolf, D. A.; Pereira, M.; Lau, S.; Jakobsson, J.; Bjorklund, A.; Grealish, S.; Parmar, M. (2013). "Generation of induced neurons via direct conversion in vivo". Proceedings of the National Academy of Sciences 110 (17): 7038.  
  161. ^ Niu, W.; Zang, T.; Zou, Y.; Fang, S.; Smith, D. K.; Bachoo, R.; Zhang, C. L. (2013). "In vivo reprogramming of astrocytes to neuroblasts in the adult brain". Nature Cell Biology 15 (10): 1164.  
  162. ^ Su, Z.; Niu, W.; Liu, M. L.; Zou, Y.; Zhang, C. L. (2014). "In vivo conversion of astrocytes to neurons in the injured adult spinal cord". Nature Communications 5.  
  163. ^ Najm, F. J.; Lager, A. M.; Zaremba, A.; Wyatt, K.; Caprariello, A. V.; Factor, D. C.; Karl, R. T.; Maeda, T.; Miller, R. H.; Tesar, P. J. (2013). "Transcription factor–mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells". Nature Biotechnology 31 (5): 426.  
  164. ^ Yang, N.; Zuchero, J. B.; Ahlenius, H.; Marro, S.; Ng, Y. H.; Vierbuchen, T.; Hawkins, J. S.; Geissler, R.; Barres, B. A.; Wernig, M. (2013). "Generation of oligodendroglial cells by direct lineage conversion". Nature Biotechnology 31 (5): 434.  
  165. ^ Xu, C. (2012). "Turning cardiac fibroblasts into cardiomyocytes in vivo". Trends in Molecular Medicine 18 (10): 575.  
  166. ^ Fu, J. D.; Stone, N. R.; Liu, L.; Spencer, C.  I.; Qian, L.; Hayashi, Y.; Delgado-Olguin, P.; Ding, S.; Bruneau, B. G.; Srivastava, D. (2013). "Direct Reprogramming of Human Fibroblasts toward a Cardiomyocyte-like State". Stem Cell Reports 1 (3): 235.  
  167. ^ Chen, J. X.; Krane, M.; Deutsch, M. -A.; Wang, L.; Rav-Acha, M.; Gregoire, S.; Engels, M. C.; Rajarajan, K.; Karra, R.; Abel, E. D.; Wu, J. C.; Milan, D.; Wu, S. M. (2012). "Inefficient Reprogramming of Fibroblasts into Cardiomyocytes Using Gata4, Mef2c, and Tbx5". Circulation Research 111: 50.  
  168. ^ Burridge, P. W.; Keller, G.; Gold, J. D.; Wu, J. C. (2012). "Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Reprogramming". Cell Stem Cell 10: 16.  
  169. ^ Wang, H.; Cao, N.; Spencer, C.  I.; Nie, B.; Ma, T.; Xu, T.; Zhang, Y.; Wang, X.; Srivastava, D.; Ding, S. (2014). "Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4". Cell Reports 6 (5): 951–60.  
  170. ^ Carpenter, L.; Carr, C.; Yang, C. T.; Stuckey, D. J.; Clarke, K.; Watt, S. M. (2012). "Efficient Differentiation of Human Induced Pluripotent Stem Cells Generates Cardiac Cells That Provide Protection Following Myocardial Infarction in the Rat". Stem Cells and Development 21 (6): 977.  
  171. ^ Yamada, S.; Nelson, T. J.; Kane, G. C.; Martinez-Fernandez, A.; Crespo-Diaz, R. J.; Ikeda, Y.; Perez-Terzic, C.; Terzic, A. (2013). "IPS Cell Intervention Rescues Wall Motion Disparity Achieving Biological Cardiac Resynchronization Post-Infarction". The Journal of Physiology: no.  
  172. ^ Lian, X.; Hsiao, C.; Wilson, G.; Zhu, K.; Hazeltine, L. B.; Azarin, S. M.; Raval, K. K.; Zhang, J.; Kamp, T. J.; Palecek, S. P. (2012). "Cozzarelli Prize Winner: Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling". Proceedings of the National Academy of Sciences 109 (27): E1848.  
  173. ^ Willems, E.; Cabral-Teixeira, J.; Schade, D.; Cai, W.; Reeves, P.; Bushway, P. J.; Lanier, M.; Walsh, C.; Kirchhausen, T.; Izpisua Belmonte, J. C.; Cashman, J.; Mercola, M. (2012). "Small Molecule-Mediated TGF-β Type II Receptor Degradation Promotes Cardiomyogenesis in Embryonic Stem Cells". Cell Stem Cell 11 (2): 242.  
  174. ^ Lu, T. Y.; Lin, B.; Kim, J.; Sullivan, M.; Tobita, K.; Salama, G.; Yang, L. (2013). "Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells". Nature Communications 4.  
  175. ^ Budniatzky, I., & Gepstein, L. (2014). Concise Review: Reprogramming Strategies for Cardiovascular Regenerative Medicine: From Induced Pluripotent Stem Cells to Direct Reprogramming. Stem cells translational medicine, 3(4), 448-457. doi:10.5966/sctm.2013-0163
  176. ^ Cosgrove, B. D., Gilbert, P. M., Porpiglia, E., Mourkioti, F., Lee, S. P., Corbel, S. Y., ... & Blau, H. M. (2014). Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nature medicine, 20(3), 255-264.doi:10.1038/nm.3464 PMID 24531378
  177. ^ Sousa-Victor, P.; Gutarra, S.; García-Prat, L.; Rodriguez-Ubreva, J.; Ortet, L.; Ruiz-Bonilla, V.; Jardí, M.; Ballestar, E.; González, S.; Serrano, A. L.; Perdiguero, E.; Muñoz-Cánoves, P. (2014). "Geriatric muscle stem cells switch reversible quiescence into senescence". Nature 506 (7488): 316.  
  178. ^ Hosoyama, et al. and Masatoshi Suzuki (March, 2014). Derivation of Myogenic Progenitors Directly From Human Pluripotent Stem Cells Using a Sphere-Based Culture. Stem Cells Trans Med. doi:10.5966/sctm.2013-0143
  179. ^ Zhu, S.; Rezvani, M.; Harbell, J.; Mattis, A. N.; Wolfe, A. R.; Benet, L. Z.; Willenbring, H.; Ding, S. (2014). "Mouse liver repopulation with hepatocytes generated from human fibroblasts". Nature.  
  180. ^ Abdelalim, E. M., Bonnefond, A., Bennaceur-Griscelli, A., & Froguel, P. (2014). Pluripotent Stem Cells as a Potential Tool for Disease Modelling and Cell Therapy in Diabetes. Stem Cell Reviews and Reports, 1-11. doi:10.1007/s12015-014-9503-6
  181. ^ Hrvatin, S., O’Donnell, C. W., Deng, F., et al. & Melton, D. A. (2014). Differentiated human stem cells resemble fetal, not adult, β cells. Proceedings of the National Academy of Sciences, 111(8), 3038-3043. doi:10.1073/pnas.1400709111
  182. ^ Akinci E, Banga A, Tungatt K, et al. and Slack, J.M. (2013). Reprogramming of Various Cell Types to a Beta-Like State by Pdx1, Ngn3 and MafA. PLoS ONE 8(11): e82424. doi:10.1371/journal.pone.0082424
  183. ^ Chen, Y. J., Finkbeiner, S. R., Weinblatt, D., et al. & Stanger, B. Z. (2014). De Novo Formation of Insulin-Producing "Neo-β Cell Islets" from Intestinal Crypts. Cell Reports., doi:10.1016/j.celrep.2014.02.013
  184. ^ Hendry, C. E.; Vanslambrouck, J. M.; Ineson, J.; Suhaimi, N.; Takasato, M.; Rae, F.; Little, M. H. (2013). "Direct Transcriptional Reprogramming of Adult Cells to Embryonic Nephron Progenitors". Journal of the American Society of Nephrology 24 (9): 1424.  
  185. ^ Xinaris C, Benedetti V, Rizzo P, et al. and Giuseppe Remuzzi (2012) In vivo maturation of functional renal organoids formed from embryonic cell suspensions. J Am Soc Nephrol 23: 1857–1868, doi:10.1681/ASN.2012050505
  186. ^ Yin, L.; Ohanyan, V.; Fen Pung, Y.; Delucia, A.; Bailey, E.; Enrick, M.; Stevanov, K.; Kolz, C. L.; Guarini, G.; Chilian, W. M. (2011). "Induction of Vascular Progenitor Cells from Endothelial Cells Stimulates Coronary Collateral Growth". Circulation Research 110 (2): 241.  
  187. ^ Quijada, P.; Toko, H.; Fischer, K. M.; Bailey, B.; Reilly, P.; Hunt, K. D.; Gude, N. A.; Avitabile, D.; Sussman, M. A. (2012). "Preservation of Myocardial Structure is Enhanced by Pim-1 Engineering of Bone Marrow Cells". Circulation Research 111: 77.  
  188. ^ Mohsin, S.; Khan, M.; Toko, H.; Bailey, B.; Cottage, C. T.; Wallach, K.; Nag, D.; Lee, A.; Siddiqi, S.; Lan, F.; Fischer, K. M.; Gude, N.; Quijada, P.; Avitabile, D.; Truffa, S.; Collins, B.; Dembitsky, W.; Wu, J. C.; Sussman, M. A. (2012). "Human Cardiac Progenitor Cells Engineered with Pim-I Kinase Enhance Myocardial Repair". Journal of the American College of Cardiology 60 (14): 1278.  
  189. ^ American Heart Association (2012, July 25). Adult stem cells from liposuction used to create blood vessels in the lab. ScienceDaily.
  190. ^ Wang, Z. Z.; Au, P.; Chen, T.; Shao, Y.; Daheron, L. M.; Bai, H.; Arzigian, M.; Fukumura, D.; Jain, R. K.; Scadden, D. T. (2007). "Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo". Nature Biotechnology 25 (3): 317.  
  191. ^ Samuel, R.; Daheron, L.; Liao, S.; Vardam, T.; Kamoun, W. S.; Batista, A.; Buecker, C.; Schafer, R.; Han, X.; Au, P.; Scadden, D. T.; Duda, D. G.; Fukumura, D.; Jain, R. K. (2013). "Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells". Proceedings of the National Academy of Sciences 110 (31): 12774.  
  192. ^ Zangi, L.; Lui, K. O.; von Gise, A.; Ma, Q.; Ebina, W.; Ptaszek, L. M.; Später, D.; Xu, H.; Tabebordbar, M.; Gorbatov, R.; Sena, B.; Nahrendorf, M.; Briscoe, D. M.; Li, R. A.; Wagers, A. J.; Rossi, D. J.; Pu, W. T.; Chien, K. R. (2013). "Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction". Nature Biotechnology 31 (10): 898.  
  193. ^ Zeuner, A.; Martelli, F.; Vaglio, S.; Federici, G.; Whitsett, C.; Migliaccio, A. R. (2012). "Concise Review: Stem Cell-Derived Erythrocytes as Upcoming Players in Blood Transfusion". Stem Cells 30 (8): 1587.  
  194. ^ Hirose, S. I.; Takayama, N.; Nakamura, S.; Nagasawa, K.; Ochi, K.; Hirata, S.; Yamazaki, S.; Yamaguchi, T.; Otsu, M.; Sano, S.; Takahashi, N.; Sawaguchi, A.; Ito, M.; Kato, T.; Nakauchi, H.; Eto, K. (2013). "Immortalization of Erythroblasts by c-MYC and BCL-XL Enables Large-Scale Erythrocyte Production from Human Pluripotent Stem Cells". Stem Cell Reports 1 (6): 499.  
  195. ^ Giarratana, M. -C.; Rouard, H.; Dumont, A.; Kiger, L.; Safeukui, I.; Le Pennec, P. -Y.; Francois, S.; Trugnan, G.; Peyrard, T.; Marie, T.; Jolly, S.; Hebert, N.; Mazurier, C.; Mario, N.; Harmand, L.; Lapillonne, H.; Devaux, J. -Y.; Douay, L. (2011). "Proof of principle for transfusion of in vitro-generated red blood cells". Blood 118 (19): 5071.  
  196. ^ Kobari, L.; Yates, F.; Oudrhiri, N.; Francina, A.; Kiger, L.; Mazurier, C.; Rouzbeh, S.; El-Nemer, W.; Hebert, N.; Giarratana, M. -C.; Francois, S.; Chapel, A.; Lapillonne, H.; Luton, D.; Bennaceur-Griscelli, A.; Douay, L. (2012). "Human induced pluripotent stem cells can reach complete terminal maturation: In vivo and in vitro evidence in the erythropoietic differentiation model". Haematologica 97 (12): 1795.  
  197. ^ Keerthivasan, G.; Wickrema, A.; Crispino, J. D. (2011). "Erythroblast Enucleation". Stem Cells International 2011: 1.  
  198. ^ Smith, B. W.; Rozelle, S. S.; Leung, A.; Ubellacker, J.; Parks, A.; Nah, S. K.; French, D.; Gadue, P.; Monti, S.; Chui, D. H. K.; Steinberg, M. H.; Frelinger, A. L.; Michelson, A. D.; Theberge, R.; McComb, M. E.; Costello, C. E.; Kotton, D. N.; Mostoslavsky, G.; Sherr, D. H.; Murphy, G. J. (2013). "The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation". Blood 122 (3): 376.  
  199. ^ Siddharth Shah, Xiaosong Huang, Linzhao Cheng (2014). Stem Cell-Based Approaches to Red Blood Cell Production for Transfusion. Stem Cells Trans Med; 3:346-355; doi:10.5966/sctm.2013-0054
  200. ^ Scientific Breakthrough as Artificial Blood is Created from Stem Cells
  201. ^ Figueiredo, C. A.; Goudeva, L.; Horn, P. A.; Eiz-Vesper, B.; Blasczyk, R.; Seltsam, A. (2010). "Generation of HLA-deficient platelets from hematopoietic progenitor cells". Transfusion 50 (8): 1690.  
  202. ^ Nakamura, S.; Takayama, N.; Hirata, S.; Seo, H.; Endo, H.; Ochi, K.; Fujita, K. I.; Koike, T.; Harimoto, K. I.; Dohda, T.; Watanabe, A.; Okita, K.; Takahashi, N.; Sawaguchi, A.; Yamanaka, S.; Nakauchi, H.; Nishimura, S.; Eto, K. (2014). "Expandable Megakaryocyte Cell Lines Enable Clinically Applicable Generation of Platelets from Human Induced Pluripotent Stem Cells". Cell Stem Cell.  
  203. ^ Riddell, S. R.; Greenberg, P. D. (1995). "Principles for Adoptive T Cell Therapy of Human Viral Diseases". Annual Review of Immunology 13: 545.  
  204. ^ a b Nishimura, T.; Kaneko, S.; Kawana-Tachikawa, A.; Tajima, Y.; Goto, H.; Zhu, D.; Nakayama-Hosoya, K.; Iriguchi, S.; Uemura, Y.; Shimizu, T.; Takayama, N.; Yamada, D.; Nishimura, K.; Ohtaka, M.; Watanabe, N.; Takahashi, S.; Iwamoto, A.; Koseki, H.; Nakanishi, M.; Eto, K.; Nakauchi, H. (2013). "Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation". Cell Stem Cell 12: 114.  
  205. ^ Vizcardo, R.; Masuda, K.; Yamada, D.; Ikawa, T.; Shimizu, K.; Fujii, S. I.; Koseki, H.; Kawamoto, H. (2013). "Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells". Cell Stem Cell 12: 31.  
  206. ^ a b Lei, F.; Haque, R.; Xiong, X.; Song, J. (2012). "Directed Differentiation of Induced Pluripotent Stem Cells towards T Lymphocytes". Journal of Visualized Experiments (63).  
  207. ^ Sadelain, M; Brentjens, R; Rivière, I (2013). "The basic principles of chimeric antigen receptor design". Cancer Discovery 3 (4): 388–98.  
  208. ^ Themeli, M.; Kloss, C. C.; Ciriello, G.; Fedorov, V. D.; Perna, F.; Gonen, M.; Sadelain, M. (2013). "Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy". Nature Biotechnology 31 (10): 928.  
  209. ^ Pilones, K. A.; Aryankalayil, J.; Demaria, S. (2012). "Invariant NKT Cells as Novel Targets for Immunotherapy in Solid Tumors". Clinical and Developmental Immunology 2012: 1.  
  210. ^ Watarai, H.; Yamada, D.; Fujii, S. I.; Taniguchi, M.; Koseki, H. (2012). "Induced pluripotency as a potential path towards iNKT cell-mediated cancer immunotherapy". International Journal of Hematology 95 (6): 624.  
  211. ^ Haruta, M.; Tomita, Y.; Yuno, A.; Matsumura, K.; Ikeda, T.; Takamatsu, K.; Haga, E.; Koba, C.; Nishimura, Y.; Senju, S. (2012). "TAP-deficient human iPS cell-derived myeloid cell lines as unlimited cell source for dendritic cell-like antigen-presenting cells". Gene Therapy 20 (5): 504.  
  212. ^ Xie, H.; Ye, M.; Feng, R.; Graf, T. (2004). "Stepwise Reprogramming of B Cells into Macrophages". Cell 117 (5): 663.  
    Bussmann, L. H.; Schubert, A.; Vu Manh, T. P.; De Andres, L.; Desbordes, S. C.; Parra, M.; Zimmermann, T.; Rapino, F.; Rodriguez-Ubreva, J.; Ballestar, E.; Graf, T. (2009). "A Robust and Highly Efficient Immune Cell Reprogramming System". Cell Stem Cell 5 (5): 554.
  213. ^ Hanna, J.; Markoulaki, S.; Schorderet, P.; Carey, B. W.; Beard, C.; Wernig, M.; Creyghton, M. P.; Steine, E. J.; Cassady, J. P.; Foreman, R.; Lengner, C. J.; Dausman, J. A.; Jaenisch, R. (2008). "Direct Reprogramming of Terminally Differentiated Mature B Lymphocytes to Pluripotency". Cell 133 (2): 250.  
  214. ^ Di Stefano, B.; Sardina, J. L.; Van Oevelen, C.; Collombet, S.; Kallin, E. M.; Vicent, G. P.; Lu, J.; Thieffry, D.; Beato, M.; Graf, T. (2013). "C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells". Nature 506 (7487): 235.  
  215. ^ Rapino, F.; Robles, E. F.; Richter-Larrea, J. A.; Kallin, E. M.; Martinez-Climent, J. A.; Graf, T. (2013). "C/EBPα Induces Highly Efficient Macrophage Transdifferentiation of B Lymphoma and Leukemia Cell Lines and Impairs Their Tumorigenicity". Cell Reports 3 (4): 1153.  
  216. ^ Guo, J., Feng, Y., Barnes, P., Huang, F. F., Idell, S., Su, D. M., & Shams, H. (2012). Deletion of FoxN1 in the thymic medullary epithelium reduces peripheral T cell responses to infection and mimics changes of aging. PloS one, 7(4), e34681. doi:10.1371/journal.pone.0034681
  217. ^ Sun, L., Guo, J., Brown, R., Amagai, T., Zhao, Y. and Su, D.-M. (2010), Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell, 9: 347–357. doi:10.1111/j.1474-9726.2010.00559.x
  218. ^ Nicholas Bredenkamp, Craig S. Nowell and C. Clare Blackburn (April 2014). Regeneration of the aged thymus by a single transcription factor. Development, 141, 1627-1637 doi:10.1242/dev.103614
  219. ^ a b Peng, Y.; Huang, S.; Cheng, B.; Nie, X.; Enhe, J.; Feng, C.; Fu, X. (2013). "Mesenchymal stem cells: A revolution in therapeutic strategies of age-related diseases". Ageing Research Reviews 12: 103.  
  220. ^ a b Bieback, K; Kern, S; Kocaömer, A; Ferlik, K; Bugert, P (2008). "Comparing mesenchymal stromal cells from different human tissues: Bone marrow, adipose tissue and umbilical cord blood". Bio-medical materials and engineering 18 (1 Suppl): S71–6.  
  221. ^ Efimenko, A.; Dzhoyashvili, N.; Kalinina, N.; Kochegura, T.; Akchurin, R.; Tkachuk, V.; Parfyonova, Y. (2013). "Adipose-Derived Mesenchymal Stromal Cells from Aged Patients with Coronary Artery Disease Keep Mesenchymal Stromal Cell Properties but Exhibit Characteristics of Aging and Have Impaired Angiogenic Potential". Stem Cells Translational Medicine 3: 32.  
  222. ^ Stolzing, A; Jones, E; McGonagle, D; Scutt, A (2008). "Age-related changes in human bone marrow-derived mesenchymal stem cells: Consequences for cell therapies". Mechanisms of Ageing and Development 129 (3): 163–73.  
  223. ^ Irina Eberle, Mohsen Moslem, Reinhard Henschler, Tobias Cantz (2012) Engineered MSCs from Patient-Specific iPS Cells. Advances in Biochemical Engineering Biotechnology
  224. ^ Chen, Y. S.; Pelekanos, R. A.; Ellis, R. L.; Horne, R.; Wolvetang, E. J.; Fisk, N. M. (2012). "Small Molecule Mesengenic Induction of Human Induced Pluripotent Stem Cells to Generate Mesenchymal Stem/Stromal Cells". Stem Cells Translational Medicine 1 (2): 83.  
  225. ^ Hynes, K; Menicanin, D; Han, J; Marino, V; Mrozik, K; Gronthos, S; Bartold, P. M. (2013). "Mesenchymal stem cells from iPS cells facilitate periodontal regeneration". Journal of Dental Research 92 (9): 833–9.  
  226. ^ iPSC for Dental Tissue Regeneration
  227. ^ Lai, R. C.; Yeo, R. W. Y.; Tan, S. S.; Zhang, B.; Yin, Y.; Sze, N. S. K.; Choo, A.; Lim, S. K. (2013). "Mesenchymal Stem Cell Therapy". p. 39.  
    Lai, R. C.; Yeo, R. W. Y.; Tan, K. H.; Lim, S. K. (2013). "Exosomes for drug delivery — a novel application for the mesenchymal stem cell". Biotechnology Advances 31 (5): 543.

    Kosaka, N.; Takeshita, F.; Yoshioka, Y.; Hagiwara, K.; Katsuda, T.; Ono, M.; Ochiya, T. (2013). "Exosomal tumor-suppressive microRNAs as novel cancer therapy". Advanced Drug Delivery Reviews 65 (3): 376.
  228. ^ Jumabay, M.; Abdmaulen, R.; Ly, A.; Cubberly, M. R.; Shahmirian, L. J.; Heydarkhan-Hagvall, S.; Dumesic, D. A.; Yao, Y.; Bostrom, K. I. (2014). "Pluripotent Stem Cells Derived from Mouse and Human White Mature Adipocytes". Stem Cells Translational Medicine 3 (2): 161.  
  229. ^ Poloni, A.; Maurizi, G.; Leoni, P.; Serrani, F.; Mancini, S.; Frontini, A.; Zingaretti, M. C.; Siquini, W.; Sarzani, R.; Cinti, S. (2012). "Human Dedifferentiated Adipocytes Show Similar Properties to Bone Marrow-Derived Mesenchymal Stem Cells". Stem Cells 30 (5): 965.  
  230. ^ Shen, J. F.; Sugawara, A; Yamashita, J; Ogura, H; Sato, S (2011). "Dedifferentiated fat cells: An alternative source of adult multipotent cells from the adipose tissues". International Journal of Oral Science 3 (3): 117–24.  
  231. ^ Melief, S. M.; Zwaginga, J. J.; Fibbe, W. E.; Roelofs, H. (2013). "Adipose Tissue-Derived Multipotent Stromal Cells Have a Higher Immunomodulatory Capacity Than Their Bone Marrow-Derived Counterparts". Stem Cells Translational Medicine 2 (6): 455.  
  232. ^ Cheng, A.; Hardingham, T. E.; Kimber, S. J. (2013). "Generating Cartilage Repair from Pluripotent Stem Cells". Tissue Engineering Part B: Reviews: 131030093023007.  
  233. ^ Outani, H.; Okada, M.; Yamashita, A.; Nakagawa, K.; Yoshikawa, H.; Tsumaki, N. (2013). "Direct Induction of Chondrogenic Cells from Human Dermal Fibroblast Culture by Defined Factors". PLoS ONE 8 (10): e77365.  
  234. ^ a b Crompton, J. G.; Rao, M.; Restifo, N. P. (2013). "Memoirs of a Reincarnated T Cell". Cell Stem Cell 12: 6.  
  235. ^ Tan, H. -K.; Toh, C. -X. D.; Ma, D.; Yang, B.; Liu, T. M.; Lu, J.; Wong, C. -W.; Tan, T. -K.; Li, H.; Syn, C.; Tan, E. -L.; Lim, B.; Lim, Y. -P.; Cook, S. A.; Loh, Y. -H. (2014). "Human Finger-Prick Induced Pluripotent Stem Cells Facilitate the Development of Stem Cell Banking". Stem Cells Translational Medicine.  
  236. ^ Okita, K.; Yamakawa, T.; Matsumura, Y.; Sato, Y.; Amano, N.; Watanabe, A.; Goshima, N.; Yamanaka, S. (2013). "An Efficient Nonviral Method to Generate Integration-Free Human-Induced Pluripotent Stem Cells from Cord Blood and Peripheral Blood Cells". Stem Cells 31 (3): 458.  
  237. ^ Geti, I.; Ormiston, M. L.; Rouhani, F.; Toshner, M.; Movassagh, M.; Nichols, J.; Mansfield, W.; Southwood, M.; Bradley, A.; Rana, A. A.; Vallier, L.; Morrell, N. W. (2012). "A Practical and Efficient Cellular Substrate for the Generation of Induced Pluripotent Stem Cells from Adults: Blood-Derived Endothelial Progenitor Cells". Stem Cells Translational Medicine 1 (12): 855.  
  238. ^ Staerk, J.; Dawlaty, M. M.; Gao, Q.; Maetzel, D.; Hanna, J.; Sommer, C. A.; Mostoslavsky, G.; Jaenisch, R. (2010). "Reprogramming of Human Peripheral Blood Cells to Induced Pluripotent Stem Cells". Cell Stem Cell 7: 20.  
    Park, T. S.; Huo, J. S.; Peters, A.; Talbot, C. C.; Verma, K.; Zimmerlin, L.; Kaplan, I. M.; Zambidis, E. T. (2012). "Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors". PLoS ONE 7 (8): e42838.
  239. ^ Yoshikawa, K.; Naitoh, M.; Kubota, H.; Ishiko, T.; Aya, R.; Yamawaki, S.; Suzuki, S. (2013). "Multipotent stem cells are effectively collected from adult human cheek skin". Biochemical and Biophysical Research Communications 431: 104.  
  240. ^ Zhou, T.; Benda, C.; Duzinger, S.; Huang, Y.; Li, X.; Li, Y.; Guo, X.; Cao, G.; Chen, S.; Hao, L.; Chan, Y. -C.; Ng, K. -M.; Cy Ho, J.; Wieser, M.; Wu, J.; Redl, H.; Tse, H. -F.; Grillari, J.; Grillari-Voglauer, R.; Pei, D.; Esteban, M. A. (2011). "Generation of Induced Pluripotent Stem Cells from Urine". Journal of the American Society of Nephrology 22 (7): 1221.  
    Zhou, T.; Benda, C.; Dunzinger, S.; Huang, Y.; Ho, J. C.; Yang, J.; Wang, Y.; Zhang, Y.; Zhuang, Q.; Li, Y.; Bao, X.; Tse, H. F.; Grillari, J.; Grillari-Voglauer, R.; Pei, D.; Esteban, M. A. (2012). "Generation of human induced pluripotent stem cells from urine samples". Nature Protocols 7 (12): 2080.

    Wang, L.; Wang, L.; Huang, W.; Su, H.; Xue, Y.; Su, Z.; Liao, B.; Wang, H.; Bao, X.; Qin, D.; He, J.; Wu, W.; So, K. F.; Pan, G.; Pei, D. (2012). "Generation of integration-free neural progenitor cells from cells in human urine". Nature Methods 10: 84.
    Cai J, Zhang Y, Liu P, Chen S, Wu X, Sun Y, Li A, Huang K et al (2013)Generation of tooth-like structures from integration-free human urine induced pluripotent stem cells. Cell Regeneration , 2:6
  241. ^ Bharadwaj, S.; Liu, G.; Shi, Y.; Wu, R.; Yang, B.; He, T.; Fan, Y.; Lu, X.; Zhou, X.; Liu, H.; Atala, A.; Rohozinski, J.; Zhang, Y. (2013). "Multipotential differentiation of human urine-derived stem cells: Potential for therapeutic applications in urology". Stem Cells 31 (9): 1840.  
  242. ^ Wang, Y.; Liu, J.; Tan, X.; Li, G.; Gao, Y.; Liu, X.; Zhang, L.; Li, Y. (2012). "Induced Pluripotent Stem Cells from Human Hair Follicle Mesenchymal Stem Cells". Stem Cell Reviews and Reports 9 (4): 451.  
  243. ^ Schnabel, L. V.; Abratte, C. M.; Schimenti, J. C.; Southard, T. L.; Fortier, L. A. (2012). "Genetic background affects induced pluripotent stem cell generation". Stem Cell Research & Therapy 3 (4): 30.  
  244. ^ Panopoulos, A. D.; Ruiz, S.; Yi, F.; Herrerías, A. D.; Batchelder, E. M.; Belmonte, J. C. I. (2011). "Rapid and Highly Efficient Generation of Induced Pluripotent Stem Cells from Human Umbilical Vein Endothelial Cells". PLoS ONE 6 (5): e19743.  
  245. ^ a b Polo, J. M.; Liu, S.; Figueroa, M. E.; Kulalert, W.; Eminli, S.; Tan, K. Y.; Apostolou, E.; Stadtfeld, M.; Li, Y.; Shioda, T.; Natesan, S.; Wagers, A. J.; Melnick, A.; Evans, T.; Hochedlinger, K. (2010). "Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells". Nature Biotechnology 28 (8): 848.  
  246. ^ Miura, K.; Okada, Y.; Aoi, T.; Okada, A.; Takahashi, K.; Okita, K.; Nakagawa, M.; Koyanagi, M.; Tanabe, K.; Ohnuki, M.; Ogawa, D.; Ikeda, E.; Okano, H.; Yamanaka, S. (2009). "Variation in the safety of induced pluripotent stem cell lines". Nature Biotechnology 27 (8): 743.  
    Liang, Y.; Zhang, H.; Feng, Q. S.; Cai, M. B.; Deng, W.; Qin, D.; Yun, J. P.; Tsao, G. S. W.; Kang, T.; Esteban, M. A.; Pei, D.; Zeng, Y. X. (2013). "The propensity for tumorigenesis in human induced pluripotent stem cells is related with genomic instability". Chinese Journal of Cancer 32 (4): 205.
  247. ^ Kim, K.; Doi, A.; Wen, B.; Ng, K.; Zhao, R.; Cahan, P.; Kim, J.; Aryee, M. J.; Ji, H.; Ehrlich, L. I. R.; Yabuuchi, A.; Takeuchi, A.; Cunniff, K. C.; Hongguang, H.; McKinney-Freeman, S.; Naveiras, O.; Yoon, T. J.; Irizarry, R. A.; Jung, N.; Seita, J.; Hanna, J.; Murakami, P.; Jaenisch, R.; Weissleder, R.; Orkin, S. H.; Weissman, I. L.; Feinberg, A. P.; Daley, G. Q. (2010). "Epigenetic memory in induced pluripotent stem cells". Nature 467 (7313): 285.  
  248. ^ Kim, K.; Zhao, R.; Doi, A.; Ng, K.; Unternaehrer, J.; Cahan, P.; Hongguang, H.; Loh, Y. H.; Aryee, M. J.; Lensch, M. W.; Li, H.; Collins, J. J.; Feinberg, A. P.; Daley, G. Q. (2011). "Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells". Nature Biotechnology 29 (12): 1117.  
  249. ^ Bar-Nur, O.; Russ, H. A.; Efrat, S.; Benvenisty, N. (2011). "Epigenetic Memory and Preferential Lineage-Specific Differentiation in Induced Pluripotent Stem Cells Derived from Human Pancreatic Islet Beta Cells". Cell Stem Cell 9: 17.  
  250. ^ Denker, H. W. (2012). "Time to Reconsider Stem Cell Induction Strategies". Cells 1 (4): 1293.  


This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.