Induced pluripotent stem cells11/13/2023 A group led by Clive Svendsen generated iPSCs from a young boy with spinal muscular atrophy and, subsequently, differentiated the iPSCs into neurons. 23 reported that the human cells could also be successfully rewound into stem cell-like state. Several findings have demonstrated that iPSCs can be differentiated into all kinds of tissue in mice, including cardiovascular and hematopoietic lineages, 18 sperm, 19, 20 cardiomyocytes (CMs), 21 and retinal cells. 16 cured sickle cell anemic mice by autologous iPSC therapy, and Stadtfeld and Hochedlinger 17 cloned mouse iPSCs. 15 used Thomason's cluster consisting of a slightly different combination of transcription factors (Lin28, Nanog, Oct4, Sox2) to reprogram human embryonic, neonatal, and adult fibroblasts into iPSCs, Hanna et al. 8 In astonishment to the pioneering report of iPSCs, scientists quickly tried to reproduce and extend the work. The nuclear reprogramming involves the transduction of four transcription factors-Oct4, Sox2, Klf4, and c-Myc (OSKM) -into somatic cells that led to the generation of iPSCs. c-Myc, cellular-Myelocytomatosis Klf4, Krüppel-like factor 4 Oct4, octamer-binding transcription factor 4 Sox2, SRY (sex determining region Y)-box 2. Ectopic expression of the four defined transcription factors associated with pluripotency (Oct4, Sox2, Klf4, and c-Myc) reverses the unipotency state into a pluripotency state. In addition, the potential applications of iPSCs in cell replacement therapy and the synergy of iPSCs and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing tool in therapeutics research are also reviewed. This review discusses the scientific framework that led to the reprogramming of induced pluripotent stem cells (iPSCs), the roles of the OSKM in reprogramming the mature differentiated cells into iPSCs, and the benefits and drawbacks of the reprogramming strategies. Takahashi and Yamanaka 9 were the first to demonstrate that the pluripotent stem cells could be induced from the adult fibroblasts by introducing four transcription factors, octamer-binding transcription factor 3/4 (Oct3/4), SRY (sex determining region Y)-box 2 (Sox2), Krüppel-like factor 4 (Klf4), and cellular-Myelocytomatosis (c-Myc) (OSKM). 8 Extensive research has been conducted in identifying these factors. It was hypothesized that the factors that play important roles in the maintenance of ESC identity also play pivotal roles in the induction of pluripotency in the somatic cells. However, little is known about this process. The conservation of genome during development serves as a basis of principle for nuclear reprogramming. The transplanted genome is reprogrammed into a pluripotent state, whereby the egg undergoes cell division and a cloned animal is produced. The nucleus of a differentiated cell is transplanted into an enucleated egg in meiotic metaphase by nuclear transfer. 6 These momentous findings concluded that differentiated cells still retain the genetic memory that is important for an organism's development and that oocytes contain factors that can reprogram the mature cell's nuclei. 4, 5 More than 30 years later, Dolly the sheep was cloned from an adult somatic cell using nuclear transfer technology. Gurdon entirely altered this paradigm by producing a fully functional tadpole from an unfertilized egg containing a nucleus from a differentiated intestinal epithelium cell of a mature frog ( Fig. It was initially thought that the genome of a mature cell is everlastingly locked in a somatic state and unable to revert into a fully ESC-like state. The ethical and legislative debates revolving around the use of human embryo in research have been circumvented by the advancements in nuclear reprogramming. 2 However, human ESC-related research is ethically controversial because it involves the destruction of human embryo. 1 ESCs offer tremendous potential applications in biomedical research and regenerative medicine, opening new avenues for therapeutic strategies aimed at cell replacement in degenerative, traumatic, and ischemic disorders. These cells are pluripotent, that is, they have an indefinite ability to self-renew while maintaining the potential to differentiate into all cell types. Human embryonic stem cells (ESCs) are derived from the inner cell mass of a developing embryo at the blastocyst stage.
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