Induced pluripotent stem cell

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cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease. In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy subjects, providing insight into the pathophysiology of the disease. An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of diseases. Managed by the

563:(cancer-causing genes) may potentially be triggered. In February 2008, scientists announced the discovery of a technique that could remove oncogenes after the induction of pluripotency, thereby increasing the potential use of iPS cells in human diseases. In another study, Yamanaka reported that one can create iPSCs without the oncogene c-Myc. The process took longer and was not as efficient, but the resulting chimeras did not develop cancer. Inactivation or deletion of the tumor suppressor p53, which is a key regulator of cancer, significantly increases reprogramming efficiency. Thus there seems to be a tradeoff between reprogramming efficiency and tumor generation. 745: 1457: 689:). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the 1028:

integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells. Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

6070: 590: 174: 45: 6450: 394:, fail to elicit induction, thus demonstrating the exclusiveness of Oct-3/4 to the induction process. Schöler showed that Oct4 overexpression during reprogramming causes epigenetic changes deteriorating the quality of iPSCs. Comparing to OSKM (Oct4, Sox2, Klf4 and c-Myc) new SKM (Sox2, Klf4 and c-Myc) reprogramming generates iPSCs with developmental potential equivalent to embryonic stem cell, as determined by their ability to generate all-iPSC mice through 1049:, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment. Furthermore, combining hiPSC technology and small molecule or genetically encoded voltage and calcium indicators provided a large-scale and high-throughput platform for cardiovascular drug safety screening. 736:

mechanisms have been proposed. ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhance the efficiency of induced pluripotency by acting downstream of c-Myc. MicroRNAs can also block expression of repressors of Yamanaka's four transcription factors, and there may be additional mechanisms induce reprogramming even in the absence of added exogenous transcription factors.

933:: iPS cells from mouse fetal fibroblasts injected into tetraploid blastocysts (which themselves can only form extra-embryonic tissues) can form whole, non-chimeric, fertile mice, although with low success rate. The efficiency of all-PSC mouse production could boosted by a short exposure of pluripotent stem cell line to an episomal plasmid encoding for engineered Sox2 and Klf4 (SK cocktail). 617:(HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanaka's traditional transcription factor method). The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of 637:(MET) process in which fibroblasts are pushed to a stem-cell like state, Ding's group identified two chemicals – ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 – which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, 273:, published studies that substantially improved on the reprogramming approach, giving rise to iPSCs that were indistinguishable from ESCs. Unlike the first generation of iPSCs, these second generation iPSCs produced viable chimeric mice and contributed to the mouse germline, thereby achieving the 'gold standard' for pluripotent stem cells. 673:

its own genes into the targeted host and avoids the potential for insertional mutagenesis. In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells. Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

1013:, which indicated that the cells were tolerated by the immune system. In 2013, Araki et al. attempted to reproduce the conclusion obtained by Zhou et al. using a different procedure. They took cells from a chimera that had been grown from IPSC clones and a mouse embryo, this tissue was then transplanted into 485:: In embryonic stem cells, Nanog, along with Oct-3/4 and Sox2, is necessary in promoting pluripotency. Therefore, it was surprising when Yamanaka et al. reported that Nanog was unnecessary for induction although Thomson et al. has reported it is possible to generate iPS cells with Nanog as one of the factors. 1184:

On March 9, 2018, the Specified Regenerative Medicine Committee of Osaka University officially approved the world's first clinical research plan to transplant a "myocardial sheet" made from iPS cells into the heart of patients with severe heart failure. Osaka University announced that it had filed an

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for a few days, the liver buds were transplanted into mice where the 'liver' quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the

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A more recent study on motor functional recovery after spinal cord injuries in mice showed that after human-induced pluripotent stem cells were transplanted into the mice, the cells differentiated into three neural lineages in the spinal cord. The cells stimulated regrowth of the damaged spinal cord,

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in the plasma membrane in order to increase reprogramming efficiency. Deng et al. of Beijing University reported in July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse

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Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. To identify the genes necessary for reprogramming, the researchers removed one factor at a time from the pool of twenty-four. By this process, they identified four

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A non-genetic method of producing iPSCs has been demonstrated using recombinant proteins, but its efficiency was quite low. However, refinements to this methodology yielding higher efficiency may lead to production of safer iPSCs. Other approaches such as using adenoviruses or plasmids are generally

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Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid. The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed

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that can mimic the effects of transcription factors. These compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which

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Obtaining fibroblasts to produce iPSCs involves a skin biopsy, and there has been a push towards identifying cell types that are more easily accessible. In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck. In 2010, iPSCs were derived from peripheral

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In June 2014, Takara Bio received technology transfer from iHeart Japan, a venture company from Kyoto University's iPS Cell Research Institute, to make it possible to exclusively use technologies and patents that induce differentiation of iPS cells into cardiomyocytes in Asia. The company announced

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mice. They conducted a similar trial using ES cells instead of IPSC clone and compared the results. Findings indicate that there was no significant difference in the immunogenic response produced by the IPS cells and the ES cells. Furthermore, Araki et al. reported little or no immunogenic response

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implicated in cancer. Yamanaka et al. and Jaenisch et al. demonstrated that c-myc is a factor implicated in the generation of mouse iPS cells and Yamanaka et al. demonstrated it was a factor implicated in the generation of human iPS cells. However, Thomson et al., Yamanaka et al. usage of the "myc"

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of the Klf family of transcription factors was initially identified by Yamanaka et al. and confirmed by Jaenisch et al. As a factor for the generation of mouse iPS cells and was demonstrated by Yamanaka et al. as a factor for generation of human iPS cells. However, Thomson et al. reported that Klf4

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cells could be used to generate transplants without the risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific

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Since iPSCs can only be produced with high efficiency at this time using modifications, they are generally predicted to be less safe and more tumorigenic than hESC. All the genes that have been shown to promote iPSC formation have also been linked to cancer in one way or another. Some of the genes

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were found to be extremely similar between ES and iPS cells. The generated iPSCs were remarkably similar to naturally isolated pluripotent stem cells (such as mouse and human embryonic stem cells, mESCs and hESCs, respectively) in the following respects, thus confirming the identity, authenticity,

693:. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving footprint mutations in the host cell genome. The PiggyBac Transposon System involves the re-excision of exogenous genes, which eliminates the issue of insertional mutagenesis. 672:

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of

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An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of

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Genomic Insertion: genomic integration of the transcription factors limits the utility of the transcription factor approach because of the risk of mutations being inserted into the target cell's genome. A common strategy for avoiding genomic insertion has been to use a different vector for input.

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cells were reprogrammed into iPS cells in Yamanaka's original mouse study was 0.01–0.1%. The low efficiency rate may reflect the need for precise timing, balance, and absolute levels of expression of the reprogramming genes. It may also suggest a need for rare genetic or epigenetic changes in the

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Concern regarding the immunogenicity of IPS cells arose in 2011 when Zhou et al. performed a study involving a teratoma formation assay and demonstrated that IPS cells produced an immune response strong enough to cause rejection of the cells. When a similar procedure was performed on genetically

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An important area for future studies in the iPSC field is directly testing iPSC tumorigenicity using methods that mimic the approaches that would be used for regenerative medicine therapies. Such studies are crucial since iPSCs not only form teratoma, but also mice derived from iPSCs have a high

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by preventing the activity of expression proteins, or by recruiting enzymes that interfere with expression. Thus, methylation of a gene effectively silences it by preventing transcription. Promoters of pluripotency-associated genes, including Oct-3/4, Rex1, and Nanog, were demethylated in iPSCs,

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are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Measuring variations in microRNA expression in iPS cells can be used to predict their differentiation potential. Addition of microRNAs can also be used to enhance iPS potential. Several

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somatic cells into stem cells which they called CiPS cells with the efficiency – at 0.2% – comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.

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maintained myelination, and formed synapses. These positive outcomes were observed for over 112 days after the spinal cord injury, without tumor formation. Nevertheless, a follow-up study by the same group showed distinct clones of human-induced pluripotent stem cells eventually formed tumors.

539:) complex. Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs. Depletion of Mbd3, on the other hand, improves reprogramming efficiency, that results in deterministic and synchronized iPS cell reprogramming (near 100% efficiency within seven days from mouse and human cells). 1027:

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the

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completed the first successful transplant of iPS-derived retinal cells from a donor into the eye of a person with advanced macular degeneration. However it was reported that they are now having complications. The benefits of using autologous iPSCs are that there is theoretically no risk of

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iPSC derivation is typically a slow and inefficient process, taking one–two weeks for mouse cells and three–four weeks for human cells, with efficiencies around 0.01–0.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon

241:, Japan, in 2006. They hypothesized that genes important to embryonic stem cell (ESC) function might be able to induce an embryonic state in adult cells. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse 825:

Stem cell markers: iPSCs expressed cell surface antigenic markers expressed on ESCs. Human iPSCs expressed the markers specific to hESC, including SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, TRA-2-49/6E, and Nanog. Mouse iPSCs expressed SSEA-1 but not SSEA-3 nor SSEA-4, similarly to

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are compacting proteins that are structurally localized to DNA sequences that can affect their activity through various chromatin-related modifications. H3 histones associated with Oct-3/4, Sox2, and Nanog were demethylated, indicating the expression of Oct-3/4, Sox2, and

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In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for

217:, small molecules, or even non-related genes such as lineage specifiers. It is also clear that pro-mitotic factors such as C-MYC/L-MYC or repression of cell cycle checkpoints, such as p53, are conduits to creating a compliant cellular state for iPSC reprogramming. 406:: The Sox family of transcription factors is associated with maintaining pluripotency similar to Oct-3/4, although it is associated with multipotent and unipotent stem cells in contrast with Oct-3/4, which is exclusively expressed in pluripotent stem cells. While 1244:. However the trial was suspended after Japan's new regenerative medicine laws came into effect in November 2015. More specifically, an existing set of guidelines was strengthened to have the force of law (previously mere recommendations). iPSCs derived from 117:. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease. 196:

iPSCs are typically derived by introducing products of specific sets of pluripotency-associated genes, or "reprogramming factors", into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the transcription factors

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Thornton, Christopher D.; Fielding, Stuart; Karbowniczek, Kinga; Roig-Merino, Alicia; Burrows, Alysha E.; FitzPatrick, Lorna M.; Sharaireh, Aseel; Tite, John P.; Mole, Sara E.; Harbottle, Richard P.; Caproni, Lisa J.; McKay, Tristan R. (10 December 2021).

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Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure), time it takes to expand the population of starting cells, and the ability to differentiate into a given cell type.

961:, more than to any other cell type. However, on the order of a thousand sites show differences in several iPS cell lines. Half of these resemble the somatic cell line the iPS cells were derived from, the rest are iPSC-specific. Tens of regions which are 135:

Since iPSCs can be derived directly from adult tissues, they not only bypass the need for embryos, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of

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These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4). However, instead of using Fbx15 to select for pluripotent cells, the researchers used

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The table on the right summarizes the key strategies and techniques used to develop iPS cells in the first five years after Yamanaka et al.'s 2006 breakthrough. Rows of similar colors represent studies that used similar strategies for reprogramming.

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who was the first to derive human embryonic stem cells. With the same principle used in mouse reprogramming, Yamanaka's group successfully transformed human fibroblasts into iPSCs with the same four pivotal genes, Oct4, Sox2, Klf4, and cMyc, using a

815:. Colonies of iPSCs were also similar to that of ESCs. Human iPSCs formed sharp-edged, flat, tightly packed colonies similar to hESCs and mouse iPSCs formed the colonies similar to mESCs, less flat and more aggregated colonies than that of hESCs. 1275:

New clinical trials involving iPSCs are now ongoing not only in Japan, but also in the US and Europe. Research in 2021 on the trial registry Clinicaltrials.gov identified 129 trial listings mentioning iPSCs, but most were non-interventional.

919:) differentiates into extraembryonic tissues. The hollow trophoblast is unable to form a living embryo, and thus it is necessary for the embryonic stem cells within the embryoblast to differentiate and form the embryo. iPSCs were injected by 558:

Tumorigenicity: Depending on the methods used, reprogramming of adult cells to obtain iPSCs may pose significant risks that could limit their use in humans. For example, if viruses are used to genomically alter the cells, the expression of

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introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or

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also generate iPSCs, although with decreased efficiency. Velychko et al. engineered a chimeric super-reprogramming factor, Sox2-17 or "super-Sox", which enhanced or allowed generation of mouse, human, cynomolgus monkey, porcine and bovine

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Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the

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MacCarthy, Caitlin M.; Wu, Guangming; Malik, Vikas; Menuchin-Lasowski, Yotam; Velychko, Taras; Keshet, Gal; Fan, Rui; Bedzhov, Ivan; Church, George M.; Jauch, Ralf; Cojocaru, Vlad; Schöler, Hans R.; Velychko, Sergiy (December 2023).

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Serrano, Ricardo; Feyen, Dries A.M.; Bruyneel, Arne A.N.; Hnatiuk, Anna P.; Vu, Michelle M.; Amatya, Prashila L.; Perea-Gil, Isaac; Prado, Maricela; Seeger, Timon; Wu, Joseph C.; Karakikes, Ioannis; Mercola, Mark (January 2023).

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This timeline summarizes the key strategies and techniques used to develop iPS cells in the first five years after Yamanaka et al.'s 2006 breakthrough. Rows of similar colors represent studies that used similar strategies for

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McKeithan, Wesley L.; Feyen, Dries A. M.; Bruyneel, Arne A. N.; Okolotowicz, Karl J.; Ryan, Daniel A.; Sampson, Kevin J.; Potet, Franck; Savchenko, Alex; Gómez-Galeno, Jorge; Vu, Michelle; Serrano, Ricardo (5 November 2020).

348:(Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the 5829:"Information on p=roposed pilot study of the safety and feasibility of transplantation of autologous hiPSC-derived retinal pigment epithelium (RPE) cell sheets in patients with neovascular age-related macular degeneration" 904:", which consist of a core of mitotically active and differentiating hESCs and a periphery of fully differentiated cells from all three germ layers. iPSCs also form embryoid bodies and have peripheral differentiated cells. 5915: 1005:

incidence of death from malignant cancer. A 2010 paper was published in the journal Stem Cells indicating that iPS cells are far more tumorigenic than ESC, supporting the notion that iPS cell safety is a serious concern.

180:(1) Isolate and culture donor cells. (2) Transduce stem cell-associated genes into the cells by viral vectors. Red cells indicate the cells expressing the exogenous genes. (3) Harvest and culture the cells according to 1340:

A multipotent mesenchymal stem cell, when induced into pluripotence, holds great promise to slow or reverse aging phenotypes. Such anti-aging properties were demonstrated in early clinical trials in 2017. In 2020,

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In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via

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Feyen, Dries A. M.; McKeithan, Wesley L.; Bruyneel, Arne A. N.; Spiering, Sean; Hörmann, Larissa; Ulmer, Bärbel; Zhang, Hui; Briganti, Francesca; Schweizer, Michaela; Hegyi, Bence; Liao, Zhandi (21 July 2020).

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differentiation, and presence of Oct-3/4 thus gives rise to the pluripotency and differentiation potential of embryonic stem cells. Various other genes in the "Oct" family, including Oct-3/4's close relatives,

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In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted. On 4 June 2014, the lead author,

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Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, et al. (February 2013). "Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells".

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Sharma, Arun; Burridge, Paul W.; McKeithan, Wesley L.; Serrano, Ricardo; Shukla, Praveen; Sayed, Nazish; Churko, Jared M.; Kitani, Tomoya; Wu, Haodi; Holmström, Alexandra; Matsa, Elena (15 February 2017).

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Although a pint of donated blood contains about two trillion red blood cells and over 107 million blood donations are collected globally, there is still a critical need for blood for transfusion. In 2014,

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and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Human clinical trials were not expected to begin before 2016.

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activity are cornerstones of ESCs, as stem cells must self-renew as part of their definition. iPSCs were mitotically active, actively self-renewing, proliferating, and dividing at a rate equal to ESCs.

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was the initial gene used for induction by Yamanaka et al., Jaenisch et al., and Thomson et al., other transcription factors in the Sox family have been found to work as well in the induction process.

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researchers concluded after studying elderly mice that old human cells when subjected to the Yamanaka factors, might rejuvenate and become nearly indistinguishable from their younger counterparts.

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Chen Y, Lüttmann FF, Schoger E, Schöler HR, Zelarayán LC, Kim KP, et al. (September 2021). "Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice".

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McKeithan, Wesley L.; Savchenko, Alex; Yu, Michael S.; Cerignoli, Fabio; Bruyneel, Arne A. N.; Price, Jeffery H.; Colas, Alexandre R.; Miller, Evan W.; Cashman, John R.; Mercola, Mark (2017).

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Maekawa M, Yamaguchi K, Nakamura T, Shibukawa R, Kodanaka I, Ichisaka T, et al. (June 2011). "Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1".

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Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem cells, in many aspects, such as the expression of certain stem cell genes and proteins,

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further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks.

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of ~50 cell divisions. hESCs express high telomerase activity to sustain self-renewal and proliferation, and human iPSCs also demonstrate high telomerase activity and express hTERT (human

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Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, et al. (November 2008). "Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes".

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family of genes in induction of iPS cells is troubling for the eventuality of iPS cells as clinical therapies, as 25% of mice transplanted with c-myc-induced iPS cells developed lethal

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Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

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and resulted in the live birth of mice derived entirely from iPS cells, thus ending the debate over the equivalence of embryonic stem cells (ESCs) and iPS with regard to pluripotency.

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Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. (December 2007). "Induced pluripotent stem cell lines derived from human somatic cells".

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Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, et al. (July 2007). "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state".

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Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, et al. (July 2013). "Vascularized and functional human liver from an iPSC-derived organ bud transplant".

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Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, et al. (August 2008). "Generation of pluripotent stem cells from adult mouse liver and stomach cells".

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Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, et al. (March 2011). "Modelling the long QT syndrome with induced pluripotent stem cells".

4370:"Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET" 1284:

To make iPSC-based regenerative medicine technologies available to more patients, it is necessary to create universal iPSCs that can be transplanted independently of

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that spontaneously began beating. Cardiomyocytes expressed TnTc, MEF2C, MYL2A, MYHCβ, and NKX2.5. Stem cell-associated genes were downregulated after differentiation.

1169:, can be mass-produced using chemically defined differentiation protocols. These protocols typically modulate the same developmental signaling pathways required for 1122:

of damaged heart without tumor-formation was demonstrated in mice and was successful if the intervention was carried out immediately before or after a heart attack.

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Human iPS cells colonies. The spindle-shaped cells in the background are mouse fibroblast cells. Only those cells comprising the center colony are human iPS cells.

124:. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) of the pre-implantation stage embryo, there has been much 253:

factors, Oct4, Sox2, cMyc, and Klf4, which were each necessary and together sufficient to generate ESC-like colonies under selection for reactivation of Fbx15.

4742:"Human Induced Pluripotent Stem Cell-Derived Cardiac Cell Sheets Expressing Genetically Encoded Voltage Indicator for Pharmacological and Arrhythmia Studies" 3404:

Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, et al. (August 2013). "Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds".

509:: Glis1 is transcription factor that can be used with Oct-3/4, Sox2 and Klf4 to induce pluripotency. It poses numerous advantages when used instead of C-myc. 3888:

Boland MJ, Hazen JL, Nazor KL, Rodriguez AR, Gifford W, Martin G, et al. (September 2009). "Adult mice generated from induced pluripotent stem cells".

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Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, et al. (October 2013). "Deterministic direct reprogramming of somatic cells to pluripotency".

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Zhou T, Benda C, Dunzinger S, Huang Y, Ho JC, Yang J, et al. (December 2012). "Generation of human induced pluripotent stem cells from urine samples".

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Grskovic M, Javaherian A, Strulovici B, Daley GQ (November 2011). "Induced pluripotent stem cells--opportunities for disease modeling and drug discovery".

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are known oncogenes, including the members of the Myc family. While omitting Myc still allows for iPSC formation, the efficiency is reduced up to 100 fold.

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Stem Cell Genes: iPSCs expressed genes expressed in undifferentiated ESCs, including Oct-3/4, Sox2, Nanog, GDF3, REX1, FGF4, ESG1, DPPA2, DPPA4, and hTERT.

281:, a gene that is functionally important in ESCs. By using this different strategy, the researchers created iPSCs that were functionally identical to ESCs. 6194: 941:

Promoter demethylation: Methylation is the transfer of a methyl group to a DNA base, typically the transfer of a methyl group to a cytosine molecule in a

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must be reformatted to that of the target cell type in order to fully reprogram a cell. However, three separate groups were able to find mouse embryonic

2065: 1138:, researchers identified 'vascular progenitor', the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the 5125:"Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature" 2786:

Luo M, Ling T, Xie W, Sun H, Zhou Y, Zhu Q, et al. (July 2013). "NuRD blocks reprogramming of mouse somatic cells into pluripotent stem cells".

213:. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, 4216:"Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection" 497:

expressed in embryonic stem cells and embryonic carcinoma cells associated with differentiation and proliferation. Thomson et al. demonstrated that

4106:"Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition" 531:

cell population or in the prolonged culture. However, recently a path was found for efficient reprogramming which required downregulation of the

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The major concern with the potential clinical application of iPSCs is their propensity to form tumors. Much the same as ESC, iPSCs readily form

398:. iPSCs with higher developmental potential could also be generated by enhancing dimerization between Oct4 and Sox2 using a chimeric Sox factor. 6430: 5101: 1191:

In October 2019, a group at Okayama University developed a model of ischemic heart disease using cardiomyocytes differentiated from iPS cells.

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when injected into immunodeficient mice. Teratoma formation is considered a major obstacle to stem-cell based regenerative medicine by the FDA.

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formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still being assessed.

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Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, et al. (September 2009). "iPS cells produce viable mice through tetraploid complementation".

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Quality of induced pluripotent stem cells is dramatically enhanced by omitting what was thought to be the most crucial reprogramming factor

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injected into laboratory animals with brain lesions were shown to migrate to the lesions and some motor function improvement was observed.

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Incomplete reprogramming: reprogramming also faces the challenge of completeness. This is particularly challenging because the genome-wide

4693:"Monitoring Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes with Genetically Encoded Calcium and Voltage Fluorescent Reporters" 6185: 5889: 613:

in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of

1130:

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers

1188:

On May 16, 2018, the clinical research plan was approved by the Ministry of Health, Labor and Welfare's expert group with a condition.

4669: 4047:"Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice" 1535:

Klimanskaya I, Chung Y, Becker S, Lu SJ, Lanza R (November 2006). "Human embryonic stem cell lines derived from single blastomeres".

621:. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of 6435: 1681: 6109:"Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells" 720:

agreed to retract both the papers after she was found to have committed 'research misconduct' as concluded in an investigation by

897:; this is unlike other tumors, which typically are of only one cell type. Teratoma formation is a landmark test for pluripotency. 5672:"Development of a model of ischemic heart disease using cardiomyocytes differentiated from human induced pluripotent stem cells" 3645: 661:

Another key strategy for avoiding problems such as tumorgenesis and low throughput has been to use alternate forms of vectors:

5537:"Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity" 5330:"Small-molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell-derived mesoderm" 1181:

the idea of selling cardiomyocytes to pharmaceutical companies and universities to help develop new drugs for heart disease.

266: 4478:"Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations" 633:. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the 6256: 3114: 1385: 1312:

system has been reported to suppress the expression of HLA class I and class II, respectively. To avoid NK cell attacks.

106:

could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir

6208: 2616: 1260:

where the degenerated RPE tissue was excised. Safety and vision restoration monitoring were to last one to three years.

1177:

and cardiac drug responses, since they exhibit the same genetic background as the patient from which they were derived.

950:

demonstrating their promoter activity and the active promotion and expression of pluripotency-associated genes in iPSCs.

338:

The generation of induced pluripotent cells is crucially dependent on the transcription factors used for the induction.

1292:. The current strategy for the creation of universal iPSCs has two main goals: to remove HLA expression and to prevent 3658: 927:

living mouse pups were created: mice with iPSC derivatives incorporated all across their bodies with 10–90% chimerism.

5174:"Tracking induced pluripotent stem cells-derived neural stem cells in the central nervous system of rats and monkeys" 3711:

Bao X, Zhu X, Liao B, Benda C, Zhuang Q, Pei D, et al. (April 2013). "MicroRNAs in somatic cell reprogramming".

3323:"Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds" 1729:

Eguizabal C, Aran B, Chuva de Sousa Lopes SM, Geens M, Heindryckx B, Panula S, Popovic M, Vassena R, Veiga A (2019).

634: 5997: 3363: 1272:

and that it eliminates the need to use embryonic stem cells. However, these iPSCs were derived from another person.

849:

Pluripotency: iPSCs were capable of differentiation in a fashion similar to ESCs into fully differentiated tissues.

2892:"Switching cell fate: the remarkable rise of induced pluripotent stem cells and lineage reprogramming technologies" 930: 841: 395: 4849:"An Automated Platform for Assessment of Congenital and Drug-Induced Arrhythmia with hiPSC-Derived Cardiomyocytes" 1677: 1207:

were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a

5487:"High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells" 4792:"High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells" 1089:). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in 303: 2521:"Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells" 1922:

Okita K, Ichisaka T, Yamanaka S (July 2007). "Generation of germline-competent induced pluripotent stem cells".

522:

Low efficiency: in general, the conversion to iPS cells has been incredibly low. For example, the rate at which

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gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound.

129: 6089: 4368:

Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, et al. (February 2013).

3106: 311:

system, while Thomson and colleagues used a different set of factors, Oct4, Sox2, Nanog, and Lin28, using a

5733:

Garber K (September 2015). "RIKEN suspends first clinical trial involving induced pluripotent stem cells".

4214:

Gutierrez-Aranda I, Ramos-Mejia V, Bueno C, Munoz-Lopez M, Real PJ, Mácia A, et al. (September 2010).

2619:

Oct4 is not only unnecessary but damaging during generation of mouse induced pluripotent stem cells (iPSCs)

1414:"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors" 374: 159:(MyoD) in reprogramming cell fate to a muscle lineage as an important precursor to the discovery of iPSCs. 21: 4957: 6481: 6218:

Allen Cell Explorer – realistic, data-driven 3D visualization of a living hiPSC in its pluri-potent state

5947:"Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis" 377:, and plays a crucial role in maintaining pluripotency. The absence of Oct-3/4 in Oct-3/4 cells, such as 3797:"Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells" 3271:"Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds" 2026:"Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution" 1332:

is left unchanged, since the 12 common HLA-C alleles are enough to cover 95% of the world's population.

294:

Reprogramming of human cells to iPSCs was reported in November 2007 by two independent research groups:

5778:"Japan's challenges of translational regenerative medicine: Act on the safety of regenerative medicine" 1253: 690: 3795:

Guenther MG, Frampton GM, Soldner F, Hockemeyer D, Mitalipova M, Jaenisch R, Young RA (August 2010).

882:

after nine weeks. Teratomas are tumors of multiple lineages containing tissue derived from the three

4277: 1456: 953:

DNA methylation globally: Human iPS cells are highly similar to ES cells in their patterns of which

6405: 6249: 6172: 5836: 1380: 1249: 856:, expressing βIII-tubulin, tyrosine hydroxylase, AADC, DAT, ChAT, LMX1B, and MAP2. The presence of 646: 3056:

Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R, et al. (April 2009).

744: 440:

was unnecessary for generation of human iPS cells and in fact failed to generate human iPS cells.

6365: 3455: 3133: 1655: 1313: 1289: 29: 5485:

Sharma A, Burridge PW, McKeithan WL, Serrano R, Shukla P, Sayed N, et al. (February 2017).

5273:"Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes" 1018:

for both cell lines. Thus, Araki et al. was unable to come to the same conclusion as Zhou et al.

6182: 5893: 5618: 5592: 4272: 4263:

Zhao T, Zhang ZN, Rong Z, Xu Y (May 2011). "Immunogenicity of induced pluripotent stem cells".

2288:"A high-efficiency system for the generation and study of human induced pluripotent stem cells" 1119: 1057:

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for

481: 357: 278: 3160:"A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity" 6415: 6370: 6360: 6344: 6195:

20Minute Video / The Discovery and Future of Induced Pluripotent Stem (iPS) Cells by Yamanaka

2091:

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (November 2007).

1317: 1233: 1082: 1070: 125: 114: 5379:"Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome" 4691:

Shinnawi R, Huber I, Maizels L, Shaheen N, Gepstein A, Arbel G, et al. (October 2015).

3586:"Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells" 900:

Embryoid body: hESCs in culture spontaneously form ball-like embryo-like structures termed "

6120: 5443: 5390: 5328:

Willems E, Spiering S, Davidovics H, Lanier M, Xia Z, Dawson M, et al. (August 2011).

5058: 5007: 4427:

Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, et al. (September 2008).

4381: 4326: 4162: 4058: 3952: 3897: 3846:"iPS cells can support full-term development of tetraploid blastocyst-complemented embryos" 3413: 3227: 3171: 3069: 3012: 2955: 2848: 2689: 2154: 1982: 1931: 1651: 1544: 1367:, a now-discredited claim of pluripotent stem cell generation by immersing cells in an acid 1301: 1269: 1099: 1078: 1046: 555:

vectors have all been explored, but these often come with the tradeoff of lower throughput.

431: 349: 103: 6074: 6069: 5711: 5644: 5377:

Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE (March 2011).

4104:

Nori S, Okada Y, Nishimura S, Sasaki T, Itakura G, Kobayashi Y, et al. (March 2015).

4045:

Nori S, Okada Y, Yasuda A, Tsuji O, Takahashi Y, Kobayashi Y, et al. (October 2011).

1867:"Safe and stable generation of induced pluripotent stem cells using doggybone DNA vectors" 1371:

Induced pluripotent stem cells vs embryonic stem cells lines obtained by SCNT (discussion)

128:

surrounding their use. Patient-matched embryonic stem cell lines can now be derived using

8: 6476: 6454: 6339: 6279: 6242: 6178:

Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4

6107:

Sarkar TJ, Quarta M, Mukherjee S, Colville A, Paine P, Doan L, et al. (March 2020).

5123:

Park TS, Bhutto I, Zimmerlin L, Huo JS, Nagaria P, Miller D, et al. (January 2014).

1359: 1342: 1297: 807:

Morphology: iPSCs were morphologically similar to ESCs. Each cell had round shape, large

614: 494: 121: 25: 6124: 6073: This article incorporates text from this source, which is available under the 5447: 5394: 5221:

Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, et al. (August 2014).

5062: 5011: 4476:

Freedman BS, Lam AQ, Sundsbak JL, Iatrino R, Su X, Koon SJ, et al. (October 2013).

4385: 4330: 4166: 4062: 3956: 3901: 3561: 3534: 3481:

Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, et al. (November 2009).

3417: 3231: 3175: 3073: 3016: 2959: 2852: 2693: 2286:

Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, Hochedlinger K (September 2008).

2158: 1986: 1935: 1832: 1703: 1548: 245:. The fibroblasts were engineered so that any cells reactivating the ESC-specific gene, 6217: 6200: 6141: 6108: 6053: 6026: 5973: 5946: 5804: 5777: 5758: 5569: 5536: 5511: 5486: 5467: 5411: 5378: 5354: 5329: 5305: 5272: 5247: 5222: 5198: 5173: 5149: 5124: 5082: 5031: 4973: 4933: 4908: 4883: 4848: 4824: 4791: 4766: 4741: 4740:

Shaheen N, Shiti A, Huber I, Shinnawi R, Arbel G, Gepstein A, et al. (June 2018).

4717: 4692: 4645: 4620: 4601: 4553: 4526: 4502: 4477: 4453: 4428: 4404: 4369: 4350: 4298: 4240: 4215: 4196: 4130: 4105: 4081: 4046: 4022: 3997: 3973: 3941:"Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells" 3940: 3921: 3821: 3796: 3772: 3747: 3615: 3507: 3482: 3437: 3379: 3295: 3270: 3251: 3192: 3159: 3090: 3057: 3033: 3000: 2981: 2916: 2891: 2872: 2821: 2768: 2715: 2594: 2545: 2520: 2501: 2453: 2428: 2404: 2379: 2360: 2312: 2287: 2178: 2024:

Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, et al. (June 2007).

2006: 1955: 1899: 1866: 1841: 1816: 1757: 1730: 1612: 1587: 1568: 1512: 1485: 965:

in size have also been found where iPS cells are not reprogrammed to the ES cell state.

945:(adjacent cytosine/guanine sequence). Widespread methylation of a gene interferes with 924: 785: 5140: 3939:

Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, et al. (March 2011).

2570:"Excluding Oct4 from Yamanaka Cocktail Unleashes the Developmental Potential of iPSCs" 2519:

Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, et al. (August 2010).

915:, and in the embryoblast, differentiate into the embryo while the blastocyst's shell ( 6410: 6146: 6058: 6027:"Current status and future perspectives of HLA-edited induced pluripotent stem cells" 5978: 5809: 5762: 5750: 5693: 5574: 5556: 5516: 5459: 5416: 5359: 5310: 5292: 5252: 5203: 5154: 5086: 5074: 5023: 4938: 4888: 4870: 4829: 4811: 4771: 4722: 4650: 4593: 4558: 4507: 4458: 4409: 4354: 4342: 4290: 4245: 4188: 4135: 4086: 4027: 3978: 3913: 3867: 3826: 3777: 3728: 3607: 3566: 3512: 3429: 3344: 3300: 3269:

Huangfu D, Maehr R, Guo W, Eijkelenboom A, Snitow M, Chen AE, Melton DA (July 2008).

3255: 3243: 3197: 3095: 3038: 2973: 2921: 2864: 2825: 2813: 2760: 2707: 2658: 2599: 2568:

Velychko S, Adachi K, Kim KP, Hou Y, MacCarthy CM, Wu G, Schöler HR (December 2019).

2550: 2505: 2493: 2458: 2409: 2378:

Staerk J, Dawlaty MM, Gao Q, Maetzel D, Hanna J, Sommer CA, et al. (July 2010).

2364: 2352: 2317: 2268: 2224: 2170: 2124: 2093:"Induction of pluripotent stem cells from adult human fibroblasts by defined factors" 2047: 1998: 1947: 1904: 1886: 1846: 1797: 1762: 1617: 1560: 1517: 1445: 1375: 1170: 1090: 1086: 528: 523: 444:

and Klf4 were found to be factors capable of generating iPS cells, and related genes

4977: 4200: 3684: 3619: 3441: 3383: 2985: 2719: 2182: 1572: 1098:

longevity of the transplanted organ in the host body (ability to integrate or avoid

860:-associated enzymes may indicate that iPSCs, like hESCs, may be differentiable into 324:

blood cells, and in 2012, iPSCs were made from renal epithelial cells in the urine.

6375: 6289: 6136: 6128: 6048: 6038: 5968: 5958: 5799: 5789: 5742: 5683: 5564: 5548: 5506: 5498: 5471: 5451: 5406: 5398: 5349: 5341: 5300: 5284: 5242: 5234: 5193: 5185: 5144: 5136: 5066: 5035: 5015: 4965: 4928: 4920: 4878: 4860: 4819: 4803: 4761: 4753: 4712: 4704: 4640: 4632: 4605: 4585: 4548: 4538: 4497: 4489: 4448: 4440: 4399: 4389: 4334: 4302: 4282: 4235: 4227: 4178: 4170: 4125: 4117: 4076: 4066: 4017: 4009: 3968: 3960: 3925: 3905: 3857: 3816: 3808: 3767: 3759: 3720: 3597: 3556: 3546: 3502: 3494: 3421: 3371: 3334: 3290: 3282: 3235: 3187: 3179: 3158:

Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, et al. (August 2009).

3085: 3077: 3028: 3020: 2963: 2911: 2903: 2876: 2856: 2803: 2795: 2772: 2750: 2742: 2697: 2648: 2589: 2581: 2540: 2532: 2485: 2448: 2440: 2399: 2391: 2344: 2307: 2299: 2258: 2214: 2162: 2114: 2104: 2037: 2010: 1990: 1939: 1894: 1878: 1836: 1828: 1789: 1752: 1742: 1607: 1599: 1552: 1507: 1497: 1435: 1425: 1264: 1154: 1065:

buds' (iPSC-LBs) were grown from a mixture of three different kinds of stem cells:

1058: 875: 238: 152: 5345: 3998:"Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine" 2907: 2702: 2677: 1959: 1817:"Research on induced pluripotent stem cells and the application in ocular tissues" 86:, who together showed in 2006 that the introduction of four specific genes (named 6356: 6284: 6229: 6212: 6189: 6177: 5502: 5288: 4807: 4757: 4708: 4121: 3058:"piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells" 2637:"Highly cooperative chimeric super-SOX induces naive pluripotency across species" 2380:"Reprogramming of human peripheral blood cells to induced pluripotent stem cells" 1139: 958: 946: 773: 622: 567: 295: 234: 110:"for the discovery that mature cells can be reprogrammed to become pluripotent." 75: 28:

of a colony of human induced pluripotent stem cells derived from a patient with

5998:"What are induced pluripotent stem cells or IPS cells & clinical prospects?" 5916:"First serious adverse reaction to iPS-derived retinal cell transplant reported" 2247:"Guidelines and techniques for the generation of induced pluripotent stem cells" 1780:

Yamanaka S (December 2013). "The winding road to pluripotency (Nobel Lecture)".

6425: 6420: 6387: 6132: 6043: 5963: 5794: 5688: 5671: 5552: 4924: 4543: 4444: 4374:

Proceedings of the National Academy of Sciences of the United States of America

4051:

Proceedings of the National Academy of Sciences of the United States of America

3862: 3845: 3812: 3551: 3339: 3322: 2653: 2636: 2585: 2444: 2427:

Loh YH, Hartung O, Li H, Guo C, Sahalie JM, Manos PD, et al. (July 2010).

2395: 2303: 2263: 2246: 2219: 2202: 2109: 2092: 2042: 2025: 1882: 1603: 1430: 1413: 1225: 1204: 868: 837: 609: 4969: 3724: 3375: 589: 261:

In June 2007, three separate research groups, including that of Yamanaka's, a

6470: 6205: 5862: 5560: 5296: 4874: 4865: 4815: 2569: 1890: 1166: 1115: 923:

into a trophoblast, and the blastocyst was transferred to recipient females.

901: 864:

neurons. Stem cell-associated genes were downregulated after differentiation.

857: 777: 608:

One of the main strategies for avoiding problems (1) and (2) has been to use

461: 222: 168: 5776:

Tobita M, Konomi K, Torashima Y, Kimura K, Taoka M, Kaminota M (June 2016).

5070: 4394: 4174: 4071: 3425: 3024: 2968: 2943: 2676:

Ali PS, Ghoshdastider U, Hoffmann J, Brutschy B, Filipek S (November 2012).

2166: 1747: 1185:

application with the Ministry of Health, Labor and Welfare on the same day.

649:

was sufficient to induce pluripotency. The acronym given for those iPSCs is

6304: 6206:

University of Oxford practical workshop on pluripotent stem cell technology

6150: 6062: 5982: 5813: 5754: 5697: 5578: 5520: 5463: 5420: 5363: 5314: 5256: 5207: 5189: 5158: 5078: 5027: 4942: 4892: 4833: 4775: 4726: 4654: 4597: 4562: 4511: 4493: 4462: 4413: 4346: 4294: 4249: 4213: 4192: 4139: 4090: 4031: 3982: 3917: 3871: 3830: 3781: 3732: 3611: 3570: 3516: 3433: 3348: 3304: 3247: 3201: 3099: 3042: 2977: 2925: 2868: 2817: 2764: 2711: 2662: 2603: 2554: 2497: 2489: 2462: 2413: 2356: 2321: 2272: 2228: 2174: 2128: 2051: 2002: 1951: 1908: 1850: 1801: 1793: 1766: 1621: 1564: 1521: 1502: 1486:"Stem Cells Applications in Regenerative Medicine and Disease Therapeutics" 1449: 1147: 1074: 920: 861: 71: 44: 37: 2944:"Generation of mouse induced pluripotent stem cells without viral vectors" 4636: 3535:"Generation of induced pluripotent stem cells using recombinant proteins" 2999:

Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K (November 2008).

2942:

Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (November 2008).

1146:

of mice, the stem cells engrafted into the retina, grew and repaired the

916: 908: 638: 501:

is a factor in iPSC generation in combination with OCT4, SOX2, and NANOG.

382: 185: 173: 107: 64: 6090:"Anti-Aging Stem Cell Treatment Proves Successful in Early Human Trials" 5746: 5455: 5402: 5019: 4338: 4286: 3964: 3909: 3239: 3183: 3081: 2860: 2746: 1994: 1943: 1556: 800:

and pluripotency of iPSCs to naturally isolated pluripotent stem cells:

477:

have been identified to induce instead of c-myc with similar efficiency.

298:

of Kyoto University, Japan, who pioneered the original iPSC method, and

144:

Yamanaka named iPSCs with a lower case "i" due to the popularity of the

6173:

With few factors, adult cells take on character of embryonic stem cells

5238: 5172:

Tang H, Sha H, Sun H, Wu X, Xie L, Wang P, et al. (October 2013).

4183: 3498: 3321:

Shi Y, Desponts C, Do JT, Hahm HS, Schöler HR, Ding S (November 2008).

2808: 2755: 2144: 1863: 1440: 1229: 1212: 1174: 1066: 912: 883: 833: 662: 578: 575: 571: 552: 548: 532: 378: 312: 308: 242: 137: 5892:. RIKEN Center for Developmental Biology. 4 April 2017. Archived from 2799: 2629: 2627: 2625: 2119: 1728: 696: 6265: 4231: 3763: 3748:"Embryonic stem cell-specific microRNAs promote induced pluripotency" 3602: 3585: 2536: 2348: 2203:"Patient-specific pluripotent stem cells become even more accessible" 1285: 1245: 962: 812: 808: 757: 402: 345: 67: 4589: 4367: 4013: 3533:

Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, et al. (May 2009).

3286: 3001:"Induced pluripotent stem cells generated without viral integration" 1256:(RPE) cells. The cell sheet would be transplanted into the affected 513: 6167: 5867: 2622: 1208: 1014: 1010: 986: 954: 942: 894: 890: 886: 879: 796: 781: 765: 761: 753: 732: 560: 466: 214: 189: 178:

A scheme of the generation of induced pluripotent stem (IPS) cells.

5890:"First donor iPSC-derived RPE cell transplantation in AMD patient" 5826: 907:

Chimeric mice: hESCs naturally reside within the inner cell mass (

5533: 4575: 3794: 2732: 2633: 1293: 969: 819: 792: 717: 666: 603: 544: 369: 341: 262: 181: 151:

In his Nobel seminar, Yamanaka cited the earlier seminal work of

4621:"Induced pluripotent stem cell technology: a decade of progress" 4527:"The human brain in a dish: the promise of iPSC-derived neurons" 2675: 1471:"The Nobel Prize in Physiology or Medicine – 2012 Press Release" 188:(lightgray). (4) A small subset of the transfected cells become 6327: 6317: 5327: 5102:"Researchers repair retinas in mice with virus-free stem cells" 1257: 1201: 1143: 853: 749: 387: 6183:

2 Minute Video from BSCRF about Induced Pluripotent Stem Cells

6168:

Center for iPS Cell Research and Application, Kyoto University

5484: 5433: 5269: 4788: 3659:"Japan researcher agrees to withdraw disputed stem cell paper" 2285: 1972: 6322: 6234: 6106: 5712:"First transfusions of "manufactured" blood planned for 2016" 5670:

Wei H, Wang C, Guo R, Takahashi K, Naruse K (December 2019).

4846: 2941: 1329: 1321: 1305: 1237: 1135: 1103: 1062: 721: 505: 498: 489: 474: 470: 423: 419: 364:, have been identified to increase the induction efficiency. 361: 246: 198: 91: 83: 79: 33: 4909:"A deep learning platform to assess drug proarrhythmia risk" 1731:"Two decades of embryonic stem cells: a historical overview" 16:

Pluripotent stem cell generated directly from a somatic cell

5775: 4905: 4690: 3745: 3483:"A chemical platform for improved induction of human iPSCs" 3268: 2678:"Recognition of the let-7g miRNA precursor by human Lin28B" 2090: 1325: 1309: 1241: 1131: 1033: 844:), a necessary component in the telomerase protein complex. 836:

are necessary to sustain cell division unrestricted by the

686: 682: 678: 618: 536: 449: 445: 441: 436: 415: 411: 407: 391: 206: 202: 156: 145: 99: 95: 5048: 4670:"Roche, Pfizer, Sanofi Plan $ 72.7 Million Stem-Cell Bank" 4475: 3938: 3456:"Major Step In Making Better Stem Cells From Adult Tissue" 3055: 2023: 414:

yields iPSCs with a similar efficiency as Sox2, and genes

5945:

Deinsberger J, Reisinger D, Weber B (11 September 2020).

5944: 4739: 3887: 2998: 2889: 1279: 748:

Three germ line cells/tissues differentiated from iPSCs:

456: 353: 270: 210: 120:

The most well-known type of pluripotent stem cell is the

87: 4997: 4103: 3746:

Judson RL, Babiarz JE, Venere M, Blelloch R (May 2009).

2890:

Selvaraj V, Plane JM, Williams AJ, Deng W (April 2010).

1534: 1039: 867:

Cardiac differentiation: iPSCs were differentiated into

318: 5223:"Chemically defined generation of human cardiomyocytes" 3115:"Cancer threat removed from stem cells, scientists say" 2518: 2475: 2377: 2334: 852:

Neural differentiation: iPSCs were differentiated into

284: 233:

Induced pluripotent stem cells were first generated by

5220: 5122: 4152: 2429:"Reprogramming of T cells from human peripheral blood" 1871:

Molecular Therapy - Methods & Clinical Development

1628: 3844:

Kang L, Wang J, Zhang Y, Kou Z, Gao S (August 2009).

1921: 1173:. These iPSC-cardiomyocytes can recapitulate genetic 5863:"Pioneering adult stem cell trial approved by Japan" 4426: 4315: 4044: 2838: 2567: 2244: 1588:"Induced Pluripotent Stem Cells Meet Genome Editing" 574:(MEF)-derived iPS cells that could be injected into 289: 113:

Pluripotent stem cells hold promise in the field of

102:), collectively known as Yamanaka factors, encoding 5676:

Biochemical and Biophysical Research Communications

5669: 5376: 4619:Shi Y, Inoue H, Wu JC, Yamanaka S (February 2017). 3480: 3157: 1365:

Stimulus-triggered acquisition of pluripotency cell

697:

Stimulus-triggered acquisition of pluripotency cell

4618: 4524: 3685:"Report on STAP Cell Research Paper Investigation" 3632:David Cyranoski for Nature News. January 29, 2014 1585: 4429:"Disease-specific induced pluripotent stem cells" 3320: 1411: 514:Challenges in reprogramming cells to pluripotency 6468: 5769: 3843: 249:, could be isolated using antibiotic selection. 4262: 3883: 3881: 3710: 3528: 3526: 3364:"Stem cells reprogrammed using chemicals alone" 3316: 3314: 3213: 3211: 2937: 2935: 2426: 2140: 2138: 1061:was reported by researchers from Japan. Human ' 1009:equivalent ES cells however, Zhou et al. found 381:and embryonic stem cells, leads to spontaneous 6431:Stem cell laws and policy in the United States 6024: 5856: 5854: 3644:Tracy Vence for the Scientist. March 11, 2014 3448: 710:stimulus-triggered acquisition of pluripotency 703:Stimulus-triggered acquisition of pluripotency 604:Mimicking transcription factors with chemicals 460:: The Myc family of transcription factors are 452:did as well, although with reduced efficiency. 331: 6250: 6100: 6020: 6018: 4482:Journal of the American Society of Nephrology 3682: 3403: 2785: 2240: 2238: 2196: 2194: 2192: 2066:"Generations of iPSCs and related references" 5726: 5171: 5165: 5116: 4991: 4684: 4569: 4469: 4420: 4361: 4309: 4256: 4207: 4146: 3878: 3532: 3523: 3474: 3397: 3311: 3262: 3208: 3151: 3049: 2992: 2932: 2883: 2832: 2779: 2726: 2669: 2512: 2469: 2420: 2371: 2279: 2245:Maherali N, Hochedlinger K (December 2008). 2135: 2084: 2017: 1966: 1915: 1696: 1640: 1407: 1405: 1403: 1401: 1001:thought to be safer than retroviral methods. 256: 5851: 3217: 3134:"Stem Cells – This Time Without the Cancer" 3131: 3125: 1579: 1528: 1477: 1165:Beating cardiac muscle cells, iPSC-derived 228: 6257: 6243: 6015: 2235: 2189: 1808: 653:(protein-induced pluripotent stem cells). 6140: 6052: 6042: 5995: 5972: 5962: 5860: 5803: 5793: 5687: 5568: 5510: 5410: 5353: 5304: 5246: 5197: 5148: 4932: 4882: 4864: 4823: 4765: 4716: 4644: 4552: 4542: 4501: 4452: 4403: 4393: 4276: 4239: 4182: 4129: 4080: 4070: 4021: 3995: 3972: 3861: 3820: 3771: 3601: 3583: 3560: 3550: 3506: 3361: 3338: 3294: 3191: 3089: 3032: 2967: 2915: 2807: 2754: 2701: 2652: 2593: 2544: 2452: 2403: 2328: 2311: 2262: 2218: 2118: 2108: 2041: 1898: 1840: 1756: 1746: 1611: 1511: 1501: 1439: 1429: 1398: 598: 373:(Pou5f1) Oct-3/4 is one of the family of 6436:Epigenetics in stem cell differentiation 5827:Riken Center for Developmental Biology. 3634:Acid bath offers easy path to stem cells 2200: 1779: 1634: 1335: 1252:were reprogrammed to differentiate into 1069:(for liver function) coaxed from iPSCs; 874:Teratoma formation: iPSCs injected into 743: 588: 172: 43: 36:, green the protein SSEA4, and blue the 20: 3650: 1814: 1670: 1412:Takahashi K, Yamanaka S (August 2006). 1236:and was to be conducted in 2014 at the 1114:In 2021, a switchable Yamanaka factors- 184:culture, using mitotically inactivated 74:. The iPSC technology was pioneered by 6469: 6087: 5732: 5099: 4667: 4525:Dolmetsch R, Geschwind D (June 2011). 3112: 1821:International Journal of Ophthalmology 1704:"山中教授の「iPS細胞」ってiPod のパクリ!?流行らせたいと頭小文字" 1280:Strategy for obtaining universal iPSCs 1238:Riken Center for Developmental Biology 669:, and naked DNA or protein compounds. 70:that can be generated directly from a 6238: 4958:"Miniature human liver grown in mice" 4955: 3706: 3704: 3702: 1586:Hockemeyer D, Jaenisch R (May 2016). 1490:International Journal of Cell Biology 1483: 1109: 1102:) and whether it will transform into 1040:Disease modeling and drug development 818:Growth properties: Doubling time and 375:octamer ("Oct") transcription factors 319:Generation from additional cell types 267:University of California, Los Angeles 32:. Red indicates transcription factor 5645:"ｉＰＳ細胞の心筋シート移植、臨床研究を国が大筋了承：朝日新聞デジタル" 3656: 1250:wet age-related macular degeneration 656: 285:Human induced pluripotent stem cells 1833:10.3980/j.issn.2222-3959.2015.04.31 1022: 13: 3699: 3584:Zhou W, Freed CR (November 2009). 3132:Swaminathan N (30 November 2007). 1194: 1052: 352:(Klf1, Klf2, Klf4, and Klf5), the 14: 6498: 6161: 6025:Koga K, Wang B, Kaneko S (2020). 5922:. 17 January 2018. Archived from 5141:10.1161/CIRCULATIONAHA.113.003000 1473:. Nobel Media AB. 8 October 2012. 1219: 1160: 764:) and goblet cells in intestine ( 635:mesenchymal-epithelial transition 396:tetraploid embryo complementation 290:Generation from human fibroblasts 6449: 6448: 6081: 6068: 5989: 5938: 5908: 5882: 5820: 1654:. 8 October 2012. Archived from 1455: 1125: 842:telomerase reverse transcriptase 791:Gene expression and genome-wide 727: 157:myoblast determination protein 1 5996:Knoepfler P (25 January 2021). 5704: 5663: 5637: 5611: 5585: 5527: 5478: 5427: 5370: 5321: 5263: 5214: 5093: 5042: 4949: 4899: 4840: 4782: 4733: 4661: 4612: 4518: 4097: 4038: 3989: 3932: 3837: 3788: 3739: 3713:Current Opinion in Cell Biology 3676: 3638: 3626: 3577: 3355: 2610: 2561: 2058: 1857: 1773: 1722: 804:Cellular biological properties 304:University of Wisconsin-Madison 6295:Induced pluripotent stem cells 6264: 5491:Science Translational Medicine 4796:Science Translational Medicine 4578:Nature Reviews. Drug Discovery 3683:Press Release (1 April 2014). 1463: 535:remodeling and deacetylation ( 269:collaboration, and a group at 192:and generate ES-like colonies. 53:Induced pluripotent stem cells 1: 6031:Inflammation and Regeneration 5346:10.1161/CIRCRESAHA.111.249540 2908:10.1016/j.tibtech.2010.01.002 2703:10.1016/j.febslet.2012.09.034 1391: 1320:inhibiting NK-cells, such as 1263:In March 2017, a team led by 162: 130:somatic cell nuclear transfer 6088:Haridy R (23 October 2017). 5861:Gallagher J (19 July 2013). 5503:10.1126/scitranslmed.aaf2584 5289:10.1016/j.celrep.2020.107925 5100:Mullin E (28 January 2014). 4808:10.1126/scitranslmed.aaf2584 4758:10.1016/j.stemcr.2018.04.006 4709:10.1016/j.stemcr.2015.08.009 4668:Gerlin A (5 December 2012). 4122:10.1016/j.stemcr.2015.01.006 3362:Cyranoski D (18 July 2013). 344:and certain products of the 7: 6201:Fact sheet on reprogramming 5714:. Gizmag.com. 23 April 2014 5599:(in Japanese). 24 June 2014 1678:"万能なiPS細胞「iPodのように普及してほしい」" 1348: 739: 356:(c-myc, L-myc, and N-myc), 332:Genes used to produce iPSCs 237:and Kazutoshi Takahashi at 78:and Kazutoshi Takahashi in 10: 6503: 6133:10.1038/s41467-020-15174-3 6044:10.1186/s41232-020-00132-9 5964:10.1038/s41536-020-00100-4 5795:10.1016/j.reth.2016.04.001 5689:10.1016/j.bbrc.2019.09.119 5651:(in Japanese). 16 May 2018 5625:(in Japanese). 16 May 2018 5593:"iPSから心筋細胞製造タカラバイオとベンチャー" 5553:10.1016/j.stem.2020.08.003 4925:10.1016/j.stem.2022.12.002 4544:10.1016/j.cell.2011.05.034 4445:10.1016/j.cell.2008.07.041 3863:10.1016/j.stem.2009.07.001 3813:10.1016/j.stem.2010.06.015 3552:10.1016/j.stem.2009.04.005 3340:10.1016/j.stem.2008.10.004 2654:10.1016/j.stem.2023.11.010 2586:10.1016/j.stem.2019.10.002 2445:10.1016/j.stem.2010.06.004 2396:10.1016/j.stem.2010.06.002 2304:10.1016/j.stem.2008.08.003 2264:10.1016/j.stem.2008.11.008 2220:10.1016/j.stem.2010.06.009 2110:10.1016/j.cell.2007.11.019 2043:10.1016/j.stem.2007.05.014 1883:10.1016/j.omtm.2021.09.018 1604:10.1016/j.stem.2016.04.013 1431:10.1016/j.cell.2006.07.024 1254:retinal pigment epithelial 1232:iPSCs was approved by the 931:Tetraploid complementation 878:mice spontaneously formed 700: 691:PiggyBac Transposon System 166: 26:Confocal microscopic image 6444: 6398: 6303: 6272: 6223:CamBioScience iPSC course 5951:npj Regenerative Medicine 4970:10.1038/nature.2013.13324 3996:Knoepfler PS (May 2009). 3725:10.1016/j.ceb.2012.12.004 3646:Call for STAP Retractions 3376:10.1038/nature.2013.13416 3113:Kaplan K (6 March 2009). 1648:"「i」PSなぜ小文字？山中さんってどんな人？" 979: 938:Epigenetic reprogramming 776:patterns, doubling time, 677:the other three factors ( 257:Second generation (mouse) 6406:Cellular differentiation 5619:"iPSで心臓治療了承高難度の再生医療へ一歩" 4866:10.3389/fphys.2017.00766 3138:Scientific American News 2201:Yamanaka S (July 2010). 1815:Guo XL, Chen JS (2015). 1381:Directed differentiation 1300:of HLA. Deletion of the 229:First generation (mouse) 6366:Hematopoietic stem cell 5071:10.1126/science.abg5159 4956:Baker M (3 July 2013). 4853:Frontiers in Physiology 4395:10.1073/pnas.1201753109 4175:10.1126/science.1154884 4072:10.1073/pnas.1108077108 3426:10.1126/science.1239278 3025:10.1126/science.1162494 2969:10.1126/science.1164270 2896:Trends in Biotechnology 2167:10.1126/science.1151526 1735:Human Reproduction Open 1248:from six patients with 1153:Labelled iPSCs-derived 968:Histone demethylation: 30:oculocutaneous albinism 5920:The Japan Times Online 5190:10.1089/cell.2012.0081 5178:Cellular Reprogramming 4494:10.1681/ASN.2012111089 3657:Lies E (4 June 2014). 2490:10.1038/nprot.2012.115 1794:10.1002/anie.201306721 1083:mesenchymal stem cells 1071:endothelial stem cells 769: 599:Alternative approaches 595: 193: 49: 41: 6487:2006 in biotechnology 6416:Stem cell controversy 6371:Mesenchymal stem cell 6361:Endothelial stem cell 6228:23 April 2019 at the 6188:18 April 2011 at the 6113:Nature Communications 1748:10.1093/hropen/hoy024 1336:Anti-aging properties 1234:Japan Ministry Health 832:Telomerase activity: 774:chromatin methylation 747: 647:poly-arginine anchors 592: 176: 115:regenerative medicine 104:transcription factors 47: 24: 6280:Embryonic stem cells 6211:8 April 2016 at the 5782:Regenerative Therapy 5735:Nature Biotechnology 5334:Circulation Research 4637:10.1038/nrd.2016.245 3752:Nature Biotechnology 3275:Nature Biotechnology 2525:Nature Biotechnology 2337:Nature Biotechnology 1503:10.1155/2016/6940283 1360:Stem cell treatments 1118:-based approach for 1079:umbilical cord blood 1047:University of Oxford 495:mRNA binding protein 148:and other products. 6340:Embryonic stem cell 6125:2020NatCo..11.1545S 5896:on 6 September 2017 5747:10.1038/nbt0915-890 5456:10.1038/nature09747 5448:2011Natur.471..225I 5403:10.1038/nature09855 5395:2011Natur.471..230Y 5104:. fiercebiotech.com 5063:2021Sci...373.1537C 5057:(6562): 1537–1540. 5020:10.1038/nature12271 5012:2013Natur.499..481T 4625:Nat Rev Drug Discov 4386:2013PNAS..110.2152S 4339:10.1038/nature11807 4331:2013Natur.494..100A 4287:10.1038/nature10135 4167:2008Sci...321..699A 4063:2011PNAS..10816825N 3965:10.1038/nature09798 3957:2011Natur.471...68L 3910:10.1038/nature08310 3902:2009Natur.461...91B 3418:2013Sci...341..651H 3240:10.1038/nature08267 3232:2009Natur.461...86Z 3184:10.1038/nature08287 3176:2009Natur.460.1149M 3082:10.1038/nature07863 3074:2009Natur.458..766W 3017:2008Sci...322..945S 2960:2008Sci...322..949O 2861:10.1038/nature12587 2853:2013Natur.502...65R 2747:10.1038/nature10106 2694:2012FEBSL.586.3986S 2159:2007Sci...318.1917Y 1995:10.1038/nature05944 1987:2007Natur.448..318W 1944:10.1038/nature05934 1936:2007Natur.448..313O 1658:on 21 November 2012 1557:10.1038/nature05142 1549:2006Natur.444..481K 1343:Stanford University 1073:(to form lining of 615:histone deacetylase 122:embryonic stem cell 38:nuclei of the cells 6482:Induced stem cells 5926:on 27 January 2018 5239:10.1038/nmeth.2999 3499:10.1038/nmeth.1393 1355:Induced stem cells 1110:Organ regeneration 784:formation, viable 770: 596: 194: 141:basis of disease. 50: 42: 6464: 6463: 6411:Stem cell therapy 6290:Cancer stem cells 5547:(5): 813–821.e6. 5497:(377): eaaf2584. 4802:(377): eaaf2584. 4746:Stem Cell Reports 4697:Stem Cell Reports 4161:(5889): 699–702. 4110:Stem Cell Reports 3462:. 19 October 2009 3170:(7259): 1149–53. 3119:Los Angeles Times 2800:10.1002/stem.1374 2647:(1): 127–147.e9. 2580:(6): 737–753.e4. 2153:(5858): 1917–20. 1782:Angewandte Chemie 1484:Mahla RS (2016). 1376:Dedifferentiation 1171:heart development 1091:fetal development 1087:connective tissue 724:on 1 April 2014. 657:Alternate vectors 6494: 6452: 6451: 6399:Related articles 6376:Neural stem cell 6285:Adult stem cells 6259: 6252: 6245: 6236: 6235: 6155: 6154: 6144: 6104: 6098: 6097: 6085: 6079: 6072: 6066: 6056: 6046: 6022: 6013: 6012: 6010: 6008: 5993: 5987: 5986: 5976: 5966: 5942: 5936: 5935: 5933: 5931: 5912: 5906: 5905: 5903: 5901: 5886: 5880: 5879: 5877: 5875: 5858: 5849: 5848: 5846: 5844: 5835:. Archived from 5824: 5818: 5817: 5807: 5797: 5773: 5767: 5766: 5730: 5724: 5723: 5721: 5719: 5708: 5702: 5701: 5691: 5667: 5661: 5660: 5658: 5656: 5641: 5635: 5634: 5632: 5630: 5615: 5609: 5608: 5606: 5604: 5589: 5583: 5582: 5572: 5531: 5525: 5524: 5514: 5482: 5476: 5475: 5431: 5425: 5424: 5414: 5374: 5368: 5367: 5357: 5325: 5319: 5318: 5308: 5267: 5261: 5260: 5250: 5218: 5212: 5211: 5201: 5169: 5163: 5162: 5152: 5120: 5114: 5113: 5111: 5109: 5097: 5091: 5090: 5046: 5040: 5039: 4995: 4989: 4988: 4986: 4984: 4953: 4947: 4946: 4936: 4903: 4897: 4896: 4886: 4868: 4844: 4838: 4837: 4827: 4786: 4780: 4779: 4769: 4752:(6): 1879–1894. 4737: 4731: 4730: 4720: 4688: 4682: 4681: 4679: 4677: 4665: 4659: 4658: 4648: 4616: 4610: 4609: 4573: 4567: 4566: 4556: 4546: 4522: 4516: 4515: 4505: 4473: 4467: 4466: 4456: 4424: 4418: 4417: 4407: 4397: 4365: 4359: 4358: 4313: 4307: 4306: 4280: 4260: 4254: 4253: 4243: 4232:10.1002/stem.471 4211: 4205: 4204: 4186: 4150: 4144: 4143: 4133: 4101: 4095: 4094: 4084: 4074: 4057:(40): 16825–30. 4042: 4036: 4035: 4025: 3993: 3987: 3986: 3976: 3936: 3930: 3929: 3885: 3876: 3875: 3865: 3841: 3835: 3834: 3824: 3792: 3786: 3785: 3775: 3764:10.1038/nbt.1535 3743: 3737: 3736: 3708: 3697: 3696: 3694: 3692: 3680: 3674: 3673: 3671: 3669: 3654: 3648: 3642: 3636: 3630: 3624: 3623: 3605: 3603:10.1002/stem.201 3581: 3575: 3574: 3564: 3554: 3530: 3521: 3520: 3510: 3478: 3472: 3471: 3469: 3467: 3452: 3446: 3445: 3401: 3395: 3394: 3392: 3390: 3359: 3353: 3352: 3342: 3318: 3309: 3308: 3298: 3266: 3260: 3259: 3215: 3206: 3205: 3195: 3155: 3149: 3148: 3146: 3144: 3129: 3123: 3122: 3110: 3104: 3103: 3093: 3068:(7239): 766–70. 3053: 3047: 3046: 3036: 2996: 2990: 2989: 2971: 2954:(5903): 949–53. 2939: 2930: 2929: 2919: 2887: 2881: 2880: 2836: 2830: 2829: 2811: 2783: 2777: 2776: 2758: 2730: 2724: 2723: 2705: 2673: 2667: 2666: 2656: 2631: 2620: 2614: 2608: 2607: 2597: 2565: 2559: 2558: 2548: 2537:10.1038/nbt.1667 2516: 2510: 2509: 2478:Nature Protocols 2473: 2467: 2466: 2456: 2424: 2418: 2417: 2407: 2375: 2369: 2368: 2349:10.1038/nbt.1503 2332: 2326: 2325: 2315: 2283: 2277: 2276: 2266: 2242: 2233: 2232: 2222: 2198: 2187: 2186: 2142: 2133: 2132: 2122: 2112: 2088: 2082: 2081: 2079: 2077: 2068:. Archived from 2062: 2056: 2055: 2045: 2021: 2015: 2014: 1981:(7151): 318–24. 1970: 1964: 1963: 1919: 1913: 1912: 1902: 1861: 1855: 1854: 1844: 1812: 1806: 1805: 1777: 1771: 1770: 1760: 1750: 1726: 1720: 1719: 1717: 1715: 1710:. 9 October 2012 1700: 1694: 1693: 1691: 1689: 1684:. 9 October 2012 1674: 1668: 1667: 1665: 1663: 1644: 1638: 1632: 1626: 1625: 1615: 1583: 1577: 1576: 1532: 1526: 1525: 1515: 1505: 1481: 1475: 1474: 1467: 1461: 1460: 1459: 1453: 1443: 1433: 1409: 1308:genes using the 1265:Masayo Takahashi 1224:The first human 1148:vascular vessels 1093:. After growing 1023:Medical research 623:calcium channels 239:Kyoto University 153:Harold Weintraub 63:) are a type of 6502: 6501: 6497: 6496: 6495: 6493: 6492: 6491: 6467: 6466: 6465: 6460: 6440: 6394: 6357:Progenitor cell 6299: 6268: 6263: 6230:Wayback Machine 6213:Wayback Machine 6197:January 8, 2008 6190:Wayback Machine 6164: 6159: 6158: 6105: 6101: 6086: 6082: 6023: 6016: 6006: 6004: 5994: 5990: 5943: 5939: 5929: 5927: 5914: 5913: 5909: 5899: 5897: 5888: 5887: 5883: 5873: 5871: 5859: 5852: 5842: 5840: 5839:on 26 June 2013 5825: 5821: 5774: 5770: 5731: 5727: 5717: 5715: 5710: 5709: 5705: 5668: 5664: 5654: 5652: 5643: 5642: 5638: 5628: 5626: 5617: 5616: 5612: 5602: 5600: 5591: 5590: 5586: 5532: 5528: 5483: 5479: 5442:(7337): 225–9. 5432: 5428: 5389:(7337): 230–4. 5375: 5371: 5326: 5322: 5268: 5264: 5219: 5215: 5170: 5166: 5121: 5117: 5107: 5105: 5098: 5094: 5047: 5043: 5006:(7459): 481–4. 4996: 4992: 4982: 4980: 4954: 4950: 4919:(1): 86–95.e4. 4904: 4900: 4845: 4841: 4787: 4783: 4738: 4734: 4689: 4685: 4675: 4673: 4672:. Bloomberg.com 4666: 4662: 4617: 4613: 4590:10.1038/nrd3577 4574: 4570: 4523: 4519: 4488:(10): 1571–86. 4474: 4470: 4425: 4421: 4366: 4362: 4325:(7435): 100–4. 4314: 4310: 4278:10.1.1.864.8029 4271:(7350): 212–5. 4261: 4257: 4212: 4208: 4151: 4147: 4102: 4098: 4043: 4039: 4014:10.1002/stem.37 3994: 3990: 3951:(7336): 68–73. 3937: 3933: 3886: 3879: 3842: 3838: 3793: 3789: 3744: 3740: 3709: 3700: 3690: 3688: 3681: 3677: 3667: 3665: 3655: 3651: 3643: 3639: 3631: 3627: 3596:(11): 2667–74. 3582: 3578: 3531: 3524: 3479: 3475: 3465: 3463: 3454: 3453: 3449: 3412:(6146): 651–4. 3402: 3398: 3388: 3386: 3360: 3356: 3319: 3312: 3287:10.1038/nbt1418 3267: 3263: 3226:(7260): 86–90. 3216: 3209: 3156: 3152: 3142: 3140: 3130: 3126: 3111: 3107: 3054: 3050: 3011:(5903): 945–9. 2997: 2993: 2940: 2933: 2888: 2884: 2847:(7469): 65–70. 2837: 2833: 2784: 2780: 2741:(7350): 225–9. 2731: 2727: 2688:(22): 3986–90. 2674: 2670: 2632: 2623: 2615: 2611: 2566: 2562: 2517: 2513: 2474: 2470: 2425: 2421: 2376: 2372: 2343:(11): 1276–84. 2333: 2329: 2284: 2280: 2243: 2236: 2199: 2190: 2143: 2136: 2089: 2085: 2075: 2073: 2072:on 30 June 2018 2064: 2063: 2059: 2022: 2018: 1971: 1967: 1930:(7151): 313–7. 1920: 1916: 1862: 1858: 1813: 1809: 1788:(52): 13900–9. 1778: 1774: 1727: 1723: 1713: 1711: 1702: 1701: 1697: 1687: 1685: 1676: 1675: 1671: 1661: 1659: 1646: 1645: 1641: 1633: 1629: 1584: 1580: 1543:(7118): 481–5. 1533: 1529: 1482: 1478: 1469: 1468: 1464: 1454: 1410: 1399: 1394: 1351: 1338: 1328:has been used. 1296:attacks due to 1282: 1222: 1205:red blood cells 1197: 1195:Red blood cells 1163: 1142:of the damaged 1128: 1112: 1059:transplantation 1055: 1053:Organ synthesis 1042: 1025: 982: 902:embryoid bodies 876:immunodeficient 742: 730: 705: 699: 659: 610:small molecules 606: 601: 568:epigenetic code 516: 462:proto-oncogenes 346:Sox gene family 334: 321: 296:Shinya Yamanaka 292: 287: 259: 235:Shinya Yamanaka 231: 171: 165: 155:on the role of 76:Shinya Yamanaka 55:(also known as 17: 12: 11: 5: 6500: 6490: 6489: 6484: 6479: 6462: 6461: 6459: 6458: 6445: 6442: 6441: 6439: 6438: 6433: 6428: 6426:Stem cell laws 6423: 6421:Stem cell line 6418: 6413: 6408: 6402: 6400: 6396: 6395: 6393: 6392: 6391: 6390: 6388:Precursor cell 6380: 6379: 6378: 6373: 6368: 6363: 6349: 6348: 6347: 6342: 6332: 6331: 6330: 6325: 6320: 6309: 6307: 6301: 6300: 6298: 6297: 6292: 6287: 6282: 6276: 6274: 6270: 6269: 6262: 6261: 6254: 6247: 6239: 6233: 6232: 6220: 6215: 6203: 6198: 6192: 6180: 6175: 6170: 6163: 6162:External links 6160: 6157: 6156: 6099: 6080: 6014: 5988: 5937: 5907: 5881: 5850: 5819: 5768: 5725: 5703: 5682:(3): 600–605. 5662: 5636: 5610: 5584: 5541:Cell Stem Cell 5526: 5477: 5426: 5369: 5320: 5262: 5227:Nature Methods 5213: 5164: 5115: 5092: 5041: 4990: 4948: 4913:Cell Stem Cell 4898: 4839: 4781: 4732: 4683: 4660: 4611: 4584:(12): 915–29. 4568: 4517: 4468: 4419: 4360: 4308: 4255: 4226:(9): 1568–70. 4206: 4145: 4096: 4037: 3988: 3931: 3896:(7260): 91–4. 3877: 3850:Cell Stem Cell 3836: 3801:Cell Stem Cell 3787: 3738: 3698: 3675: 3649: 3637: 3625: 3576: 3539:Cell Stem Cell 3522: 3487:Nature Methods 3473: 3447: 3396: 3354: 3327:Cell Stem Cell 3310: 3261: 3207: 3150: 3124: 3105: 3048: 2991: 2931: 2882: 2831: 2794:(7): 1278–86. 2778: 2725: 2668: 2641:Cell Stem Cell 2621: 2609: 2574:Cell Stem Cell 2560: 2511: 2484:(12): 2080–9. 2468: 2433:Cell Stem Cell 2419: 2384:Cell Stem Cell 2370: 2327: 2292:Cell Stem Cell 2278: 2257:(6): 595–605. 2251:Cell Stem Cell 2234: 2207:Cell Stem Cell 2188: 2134: 2083: 2057: 2030:Cell Stem Cell 2016: 1965: 1914: 1856: 1807: 1772: 1721: 1695: 1669: 1639: 1637:, p. 120. 1627: 1592:Cell Stem Cell 1578: 1527: 1476: 1462: 1396: 1395: 1393: 1390: 1389: 1388: 1383: 1378: 1373: 1368: 1362: 1357: 1350: 1347: 1337: 1334: 1281: 1278: 1226:clinical trial 1221: 1220:Clinical trial 1218: 1196: 1193: 1167:cardiomyocytes 1162: 1161:Cardiomyocytes 1159: 1127: 1124: 1111: 1108: 1054: 1051: 1041: 1038: 1024: 1021: 1020: 1019: 1006: 1002: 998: 994: 990: 981: 978: 977: 976: 975: 974: 966: 951: 936: 935: 934: 928: 905: 898: 872: 869:cardiomyocytes 865: 847: 846: 845: 838:Hayflick limit 830: 827: 823: 816: 741: 738: 729: 726: 701:Main article: 698: 695: 658: 655: 605: 602: 600: 597: 594:reprogramming. 583: 582: 564: 556: 540: 515: 512: 511: 510: 502: 493:: LIN28 is an 486: 478: 453: 428: 399: 333: 330: 320: 317: 291: 288: 286: 283: 258: 255: 230: 227: 223:reporter genes 164: 161: 15: 9: 6: 4: 3: 2: 6499: 6488: 6485: 6483: 6480: 6478: 6475: 6474: 6472: 6457: 6456: 6447: 6446: 6443: 6437: 6434: 6432: 6429: 6427: 6424: 6422: 6419: 6417: 6414: 6412: 6409: 6407: 6404: 6403: 6401: 6397: 6389: 6386: 6385: 6384: 6381: 6377: 6374: 6372: 6369: 6367: 6364: 6362: 6358: 6355: 6354: 6353: 6350: 6346: 6343: 6341: 6338: 6337: 6336: 6333: 6329: 6326: 6324: 6321: 6319: 6316: 6315: 6314: 6311: 6310: 6308: 6306: 6302: 6296: 6293: 6291: 6288: 6286: 6283: 6281: 6278: 6277: 6275: 6273:Sources/types 6271: 6267: 6260: 6255: 6253: 6248: 6246: 6241: 6240: 6237: 6231: 6227: 6224: 6221: 6219: 6216: 6214: 6210: 6207: 6204: 6202: 6199: 6196: 6193: 6191: 6187: 6184: 6181: 6179: 6176: 6174: 6171: 6169: 6166: 6165: 6152: 6148: 6143: 6138: 6134: 6130: 6126: 6122: 6118: 6114: 6110: 6103: 6095: 6091: 6084: 6078: 6076: 6071: 6064: 6060: 6055: 6050: 6045: 6040: 6036: 6032: 6028: 6021: 6019: 6003: 5999: 5992: 5984: 5980: 5975: 5970: 5965: 5960: 5956: 5952: 5948: 5941: 5925: 5921: 5917: 5911: 5895: 5891: 5885: 5870: 5869: 5864: 5857: 5855: 5838: 5834: 5830: 5823: 5815: 5811: 5806: 5801: 5796: 5791: 5787: 5783: 5779: 5772: 5764: 5760: 5756: 5752: 5748: 5744: 5740: 5736: 5729: 5713: 5707: 5699: 5695: 5690: 5685: 5681: 5677: 5673: 5666: 5650: 5646: 5640: 5624: 5620: 5614: 5598: 5594: 5588: 5580: 5576: 5571: 5566: 5562: 5558: 5554: 5550: 5546: 5542: 5538: 5530: 5522: 5518: 5513: 5508: 5504: 5500: 5496: 5492: 5488: 5481: 5473: 5469: 5465: 5461: 5457: 5453: 5449: 5445: 5441: 5437: 5430: 5422: 5418: 5413: 5408: 5404: 5400: 5396: 5392: 5388: 5384: 5380: 5373: 5365: 5361: 5356: 5351: 5347: 5343: 5339: 5335: 5331: 5324: 5316: 5312: 5307: 5302: 5298: 5294: 5290: 5286: 5283:(3): 107925. 5282: 5278: 5274: 5266: 5258: 5254: 5249: 5244: 5240: 5236: 5233:(8): 855–60. 5232: 5228: 5224: 5217: 5209: 5205: 5200: 5195: 5191: 5187: 5184:(5): 435–42. 5183: 5179: 5175: 5168: 5160: 5156: 5151: 5146: 5142: 5138: 5135:(3): 359–72. 5134: 5130: 5126: 5119: 5103: 5096: 5088: 5084: 5080: 5076: 5072: 5068: 5064: 5060: 5056: 5052: 5045: 5037: 5033: 5029: 5025: 5021: 5017: 5013: 5009: 5005: 5001: 4994: 4979: 4975: 4971: 4967: 4963: 4959: 4952: 4944: 4940: 4935: 4930: 4926: 4922: 4918: 4914: 4910: 4902: 4894: 4890: 4885: 4880: 4876: 4872: 4867: 4862: 4858: 4854: 4850: 4843: 4835: 4831: 4826: 4821: 4817: 4813: 4809: 4805: 4801: 4797: 4793: 4785: 4777: 4773: 4768: 4763: 4759: 4755: 4751: 4747: 4743: 4736: 4728: 4724: 4719: 4714: 4710: 4706: 4703:(4): 582–96. 4702: 4698: 4694: 4687: 4671: 4664: 4656: 4652: 4647: 4642: 4638: 4634: 4631:(2): 115–30. 4630: 4626: 4622: 4615: 4607: 4603: 4599: 4595: 4591: 4587: 4583: 4579: 4572: 4564: 4560: 4555: 4550: 4545: 4540: 4536: 4532: 4528: 4521: 4513: 4509: 4504: 4499: 4495: 4491: 4487: 4483: 4479: 4472: 4464: 4460: 4455: 4450: 4446: 4442: 4439:(5): 877–86. 4438: 4434: 4430: 4423: 4415: 4411: 4406: 4401: 4396: 4391: 4387: 4383: 4380:(6): 2152–6. 4379: 4375: 4371: 4364: 4356: 4352: 4348: 4344: 4340: 4336: 4332: 4328: 4324: 4320: 4312: 4304: 4300: 4296: 4292: 4288: 4284: 4279: 4274: 4270: 4266: 4259: 4251: 4247: 4242: 4237: 4233: 4229: 4225: 4221: 4217: 4210: 4202: 4198: 4194: 4190: 4185: 4180: 4176: 4172: 4168: 4164: 4160: 4156: 4149: 4141: 4137: 4132: 4127: 4123: 4119: 4116:(3): 360–73. 4115: 4111: 4107: 4100: 4092: 4088: 4083: 4078: 4073: 4068: 4064: 4060: 4056: 4052: 4048: 4041: 4033: 4029: 4024: 4019: 4015: 4011: 4008:(5): 1050–6. 4007: 4003: 3999: 3992: 3984: 3980: 3975: 3970: 3966: 3962: 3958: 3954: 3950: 3946: 3942: 3935: 3927: 3923: 3919: 3915: 3911: 3907: 3903: 3899: 3895: 3891: 3884: 3882: 3873: 3869: 3864: 3859: 3855: 3851: 3847: 3840: 3832: 3828: 3823: 3818: 3814: 3810: 3807:(2): 249–57. 3806: 3802: 3798: 3791: 3783: 3779: 3774: 3769: 3765: 3761: 3758:(5): 459–61. 3757: 3753: 3749: 3742: 3734: 3730: 3726: 3722: 3719:(2): 208–14. 3718: 3714: 3707: 3705: 3703: 3686: 3679: 3664: 3660: 3653: 3647: 3641: 3635: 3629: 3621: 3617: 3613: 3609: 3604: 3599: 3595: 3591: 3587: 3580: 3572: 3568: 3563: 3558: 3553: 3548: 3544: 3540: 3536: 3529: 3527: 3518: 3514: 3509: 3504: 3500: 3496: 3493:(11): 805–8. 3492: 3488: 3484: 3477: 3461: 3460:Science Daily 3457: 3451: 3443: 3439: 3435: 3431: 3427: 3423: 3419: 3415: 3411: 3407: 3400: 3385: 3381: 3377: 3373: 3369: 3365: 3358: 3350: 3346: 3341: 3336: 3333:(5): 568–74. 3332: 3328: 3324: 3317: 3315: 3306: 3302: 3297: 3292: 3288: 3284: 3280: 3276: 3272: 3265: 3257: 3253: 3249: 3245: 3241: 3237: 3233: 3229: 3225: 3221: 3214: 3212: 3203: 3199: 3194: 3189: 3185: 3181: 3177: 3173: 3169: 3165: 3161: 3154: 3139: 3135: 3128: 3120: 3116: 3109: 3101: 3097: 3092: 3087: 3083: 3079: 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2305: 2301: 2297: 2293: 2289: 2282: 2274: 2270: 2265: 2260: 2256: 2252: 2248: 2241: 2239: 2230: 2226: 2221: 2216: 2212: 2208: 2204: 2197: 2195: 2193: 2184: 2180: 2176: 2172: 2168: 2164: 2160: 2156: 2152: 2148: 2141: 2139: 2130: 2126: 2121: 2116: 2111: 2106: 2103:(5): 861–72. 2102: 2098: 2094: 2087: 2071: 2067: 2061: 2053: 2049: 2044: 2039: 2035: 2031: 2027: 2020: 2012: 2008: 2004: 2000: 1996: 1992: 1988: 1984: 1980: 1976: 1969: 1961: 1957: 1953: 1949: 1945: 1941: 1937: 1933: 1929: 1925: 1918: 1910: 1906: 1901: 1896: 1892: 1888: 1884: 1880: 1876: 1872: 1868: 1860: 1852: 1848: 1843: 1838: 1834: 1830: 1827:(4): 818–25. 1826: 1822: 1818: 1811: 1803: 1799: 1795: 1791: 1787: 1783: 1776: 1768: 1764: 1759: 1754: 1749: 1744: 1741:(1): hoy024. 1740: 1736: 1732: 1725: 1709: 1705: 1699: 1683: 1679: 1673: 1657: 1653: 1649: 1643: 1636: 1635:Yamanaka 2010 1631: 1623: 1619: 1614: 1609: 1605: 1601: 1598:(5): 573–86. 1597: 1593: 1589: 1582: 1574: 1570: 1566: 1562: 1558: 1554: 1550: 1546: 1542: 1538: 1531: 1523: 1519: 1514: 1509: 1504: 1499: 1495: 1491: 1487: 1480: 1472: 1466: 1458: 1451: 1447: 1442: 1437: 1432: 1427: 1424:(4): 663–76. 1423: 1419: 1415: 1408: 1406: 1404: 1402: 1397: 1387: 1384: 1382: 1379: 1377: 1374: 1372: 1369: 1366: 1363: 1361: 1358: 1356: 1353: 1352: 1346: 1344: 1333: 1331: 1327: 1323: 1319: 1315: 1311: 1307: 1303: 1299: 1295: 1291: 1287: 1277: 1273: 1271: 1266: 1261: 1259: 1255: 1251: 1247: 1243: 1239: 1235: 1231: 1227: 1217: 1214: 1210: 1206: 1203: 1192: 1189: 1186: 1182: 1178: 1176: 1172: 1168: 1158: 1156: 1151: 1149: 1145: 1141: 1137: 1133: 1126:Tissue repair 1123: 1121: 1117: 1116:reprogramming 1107: 1105: 1101: 1096: 1092: 1088: 1084: 1080: 1076: 1075:blood vessels 1072: 1068: 1064: 1060: 1050: 1048: 1037: 1035: 1029: 1016: 1012: 1007: 1003: 999: 995: 991: 988: 984: 983: 971: 967: 964: 960: 956: 952: 948: 944: 940: 939: 937: 932: 929: 926: 922: 918: 914: 910: 906: 903: 899: 896: 892: 888: 885: 881: 877: 873: 870: 866: 863: 859: 858:catecholamine 855: 851: 850: 848: 843: 839: 835: 831: 828: 824: 821: 817: 814: 810: 806: 805: 803: 802: 801: 798: 794: 789: 787: 783: 779: 778:embryoid body 775: 767: 763: 759: 755: 751: 746: 737: 734: 728:RNA molecules 725: 723: 719: 713: 711: 704: 694: 692: 688: 684: 680: 674: 670: 668: 664: 654: 652: 648: 642: 640: 636: 632: 627: 624: 620: 616: 611: 591: 587: 580: 577: 573: 569: 565: 562: 557: 554: 550: 546: 541: 538: 534: 530: 525: 521: 520: 519: 508: 507: 503: 500: 496: 492: 491: 487: 484: 483: 479: 476: 472: 468: 463: 459: 458: 454: 451: 447: 443: 438: 434: 433: 429: 425: 421: 417: 413: 409: 405: 404: 400: 397: 393: 389: 384: 380: 376: 372: 371: 367: 366: 365: 363: 359: 355: 351: 347: 343: 339: 336: 329: 325: 316: 314: 310: 305: 301: 300:James Thomson 297: 282: 280: 274: 272: 268: 264: 254: 250: 248: 244: 240: 236: 226: 224: 218: 216: 212: 208: 204: 200: 191: 187: 183: 179: 175: 170: 169:Reprogramming 160: 158: 154: 149: 147: 142: 139: 133: 131: 127: 123: 118: 116: 111: 109: 105: 101: 97: 93: 89: 85: 81: 77: 73: 69: 66: 62: 58: 54: 46: 39: 35: 31: 27: 23: 19: 6453: 6382: 6351: 6334: 6312: 6305:Cell potency 6294: 6116: 6112: 6102: 6093: 6083: 6067: 6034: 6030: 6005:. Retrieved 6001: 5991: 5954: 5950: 5940: 5928:. Retrieved 5924:the original 5919: 5910: 5898:. Retrieved 5894:the original 5884: 5872:. Retrieved 5866: 5841:. Retrieved 5837:the original 5832: 5822: 5785: 5781: 5771: 5741:(9): 890–1. 5738: 5734: 5728: 5716:. Retrieved 5706: 5679: 5675: 5665: 5653:. Retrieved 5648: 5639: 5627:. Retrieved 5622: 5613: 5601:. Retrieved 5596: 5587: 5544: 5540: 5529: 5494: 5490: 5480: 5439: 5435: 5429: 5386: 5382: 5372: 5340:(4): 360–4. 5337: 5333: 5323: 5280: 5277:Cell Reports 5276: 5265: 5230: 5226: 5216: 5181: 5177: 5167: 5132: 5128: 5118: 5106:. Retrieved 5095: 5054: 5050: 5044: 5003: 4999: 4993: 4981:. Retrieved 4961: 4951: 4916: 4912: 4901: 4856: 4852: 4842: 4799: 4795: 4784: 4749: 4745: 4735: 4700: 4696: 4686: 4674:. 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