Mouse skin fibroblasts are first reprogrammed to iPSCs by overexpression of a set of four key transcription factors (Takahashi and Yamanaka, 2006). [1] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."[2]. In contrast to organ-specific stem cells that generally have a limited potential for growth and differentiation, pluripotent stem cells, such as embryonic stem cells (ESCs) [2–4] and induced pluripotent stem (iPS) cells [5–7], have a virtually unlimited replicative capacity on culture dishes and are theoretically able to give rise to any cell type in the body. With this groundbreaking discovery, iPSC research has quickly become the foundation for a new regenerative medicine. The iPS cells are cultured in medium optimized for ES cells. In this chapter, we discuss the biological mechanisms underlying reprogramming, the evolution of reprogramming techniques, quality control of iPSCs, differentiation, and applications for iPSCs. Induced pluripotent stem cell (iPSC) technology is inspiring new ideas that range from medicine to conservation. [17][18] In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck. These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4). Systematic reviews of the literature on the osteogenic potential of iPSCs suggest that osteo-induced iPSCs demonstrate an osteogenic capability equal or superior to MSCs [9]. By studying the MET (mesenchymal-epithelial transition) 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. Mouse iPSCs expressed SSEA-1 but not SSEA-3 nor SSEA-4, similarly to mESCs. Safety and vision restoration monitoring were to last one to three years. [11][12][13][14], Reprogramming of human cells to iPSCs was reported in November 2007 by two independent research groups: Shinya Yamanaka of Kyoto University, Japan, who pioneered the original iPSC method, and James Thomson of University of Wisconsin-Madison who was the first to derive human embryonic stem cells. 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 poly-arginine anchors was sufficient to induce pluripotency. [87], The first human clinical trial using autologous iPSCs was approved by the Japan Ministry Health and was to be conducted in 2014 at the Riken Center for Developmental Biology in Kobe. Kenji Osafune, Shinya Yamanaka, in Regenerative Nephrology, 2011. At that time, science had long understood that tissue specific cells, such as skin cells or blood cells, could only create other like cells. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. iPSC derivation is typically a slow and inefficient process, taking 1–2 weeks for mouse cells and 3–4 weeks for human cells, with efficiencies around 0.01–0.1%. [88] More specifically, an existing set of guidelines was strengthened to have the force of law (previously mere recommendations). [52] 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. [89] iPSCs derived from skin cells from six patients suffering from wet age-related macular degeneration were reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. [79] These protocols typically modulate the same developmental signaling pathways required for heart development .

[71][72], A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Oct3/4, Sox2, and Nanog bind and upregulate ES-cell-specific genes such as STAT3 and ZIC3 with RNA polymerase. [32] 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 the other three factors (Oct4, Klf4, and Sox2). After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels. [51], Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem (ES) cells, in many aspects, such as the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still being assessed.[1]. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.[10]. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse fibroblasts. Therapeutic approaches using human ESCs face two major problems. They found that it increased reprogramming efficiency 100-fold (compared to Yamanaka’s traditional transcription factor method). For example, if viruses are used to genomically alter the cells, the expression of, Incomplete reprogramming: reprogramming also faces the challenge of completeness. iPSCs are induced in vitro to express certain genes and factors such as Oct3/4, Sox2, Klf4, and c-Myc that are used in ESCs. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. It will give readers a clear understanding of the current status of iPSC research and the impact of iPSCs on the future of regenerative medicine. 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: 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.

These problems have been overcome by a breakthrough experiment by Takahashi and Yamanaka. However the trial was suspended after Japan's new regenerative medicine laws came into effect in November 2015. [67][68] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy patients, providing insight into the pathophysiology of the disease. Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. [56] Further studies and new strategies should generate optimal solutions to the five main challenges.

Clone- and gene-specific aberrations of imprinting were also reported in human iPS cells [49]. Since iPS cells can be generated from somatic cells of patients, clinical approaches using iPS cells are not associated with the two above problems (use of human fertilized egg and immune rejection). [94] In 2020, Stanford University 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.

One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells. [80] These iPSC-cardiomyocytes can recapitulate genetic arrhythmias and cardiac drug responses, since they exhibit the same genetic background as the patient from which they were derived. 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. The generous participation of patients and their families in this research enables BSCRC scientists to study these diseases in the laboratory in the hope of developing new treatment technologies. Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University, Japan, in 2006. [23], Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure),[17][18] time it takes to expand the population of starting cells,[17] and the ability to differentiate into a given cell type.[24].
However, the annual increase in the number of new patients with end-stage renal disease who need a renal transplant, and the widening gap between the demand for and the supply of donor kidneys have led to a progressive shortage of donor organs for transplant. 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. For example, the rate at which, Genomic Insertion: genomic integration of the, Tumorigenicity: Depending on the methods used, reprogramming of adult cells to obtain iPSCs may pose significant risks that could limit their use in humans. 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. 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 basis of disease. [46] 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. Some of the genes are known oncogenes, including the members of the Myc family.


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