IPSCs_in_drug_development_Inoue_Yamanaka_2011_ - CLINICAL...

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Unformatted text preview: CLINICAL PHARMACOLOGY & THERAPEUTICS 1 nature publishing group STATE ART The ability of cells to differentiate into various cell types—known as “pluripotency”—is a hallmark of embryonic stem cells (ESCs). Stem cells belong to one of two major categories according to their potency of differentiation: organ-specific stem cells and pluripotent stem cells. Organ-specific stem cells generally have limited potential for growth and differentiation. In contrast, pluripotent stem cells, such as ESCs 1–3 and induced pluripo- tent stem cells (iPSCs), 4–6 replicate in culture dishes and are theoretically capable of giving rise to any of the cell types found in the body ( Figure 1 ). The development of cellular reprogramming techniques lead- ing to iPSCs has dramatically changed the landscape of stem cell research and application by providing a modality that cir- cumvents the two major issues hampering fulfillment of the great potential of human ESCs. 4–6 One is the ethical issue asso- ciated with the derivation of human ESCs from human ferti- lized eggs, and the other is the immunological incompatibility between ESC-derived donor organs or cells and the recipients because of histocompatibility–antigenic factors. 4–6 As iPSCs are transforming the field of regenerative medicine, the reprogram- ming approach is also becoming a platform for drug discovery research. DISCOVERY OF iPSCs Reprogramming inducers Transduction of four genes encoding transcription factors highly functional in ESCs (i.e., Oct3/4, Sox2, Klf4, and c-Myc) was discovered to be sufficient to trigger reprogramming of both mouse and human somatic cells and to generate cells closely resembling the respective ESCs. 4–6 The term coined for these reprogrammed ESC-like cells was “iPSCs.” 4 Subsequent research from our laboratory as well as from others has revealed several alternative methods for generating iPSCs. 7–9 Among the quartet of transcription factors involved in repro- gramming, 9 Oct3/4 is expressed specifically in ESCs and germ cells but not in somatic cells. 9 The forced expression of Oct3/4 in mouse or human Sox2-expressing neural stem cells can give rise to iPSCs, albeit with low reprogramming efficiency. 9 There are reports of iPSC generation even in the absence of the Oct3/4 transgene, but the efficiency of generation is very low. Sox2, which is a key partner of Oct3/4, is expressed almost exclusively in ESCs, germ cells, and nerve cells. The deletion of Sox2 causes the death of the embryo, suggesting its crucial role in embryogenesis. 9 Sox family proteins, including Sox2, show functional overlap with each other. Although the conventional reprogramming method requires Sox2 transgene, inhibition of the transforming growth factor beta (TGF-β) was shown to be capable of replacing Sox2 in reprogramming mouse embryonic fibroblasts....
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This note was uploaded on 04/19/2011 for the course LS 2 taught by Professor Pires during the Spring '08 term at UCLA.

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IPSCs_in_drug_development_Inoue_Yamanaka_2011_ - CLINICAL...

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