Article

Yamanaka, S. & Blau, H.M. Nuclear reprogramming to a pluripotent state by three approaches. Nature 465, 704-712

Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Nature (Impact Factor: 41.46). 06/2010; 465(7299):704-12. DOI: 10.1038/nature09229
Source: PubMed

ABSTRACT

The stable states of differentiated cells are now known to be controlled by dynamic mechanisms that can easily be perturbed. An adult cell can therefore be reprogrammed, altering its pattern of gene expression, and hence its fate, to that typical of another cell type. This has been shown by three distinct experimental approaches to nuclear reprogramming: nuclear transfer, cell fusion and transcription-factor transduction. Using these approaches, nuclei from 'terminally differentiated' somatic cells can be induced to express genes that are typical of embryonic stem cells, which can differentiate to form all of the cell types in the body. This remarkable discovery of cellular plasticity has important medical applications.

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Available from: Helen M Blau, Aug 10, 2015
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    • "As such, the research advances in neurodegenerative disease models have been well reviewed [2] [3] [4] [5]. iPSC was initially generated by reactivating nuclear reprogramming factors to reverse differentiated cells into a reprogramming state [6] [7] [8], maintaining the abilities of selfrenewal and potential differentiation into various cell types. iPSC, like ESCs, can differentiate into nearly all the cell types in the organism from which they originated, shedding light on cell-based therapies and regenerative medicine to which patient-specific iPSC could be applied in order to regenerate "
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    ABSTRACT: Possessing the ability of self-renewal with immortalization and potential for differentiation into different cell types, stem cells, particularly embryonic stem cells (ESC), have attracted significant attention since their discovery. As ESC research has played an essential role in developing our understanding of the mechanisms underlying reproduction, development, and cell (de)differentiation, significant efforts have been made in the biomedical study of ESC in recent decades. However, such studies of ESC have been hampered by the ethical issues and technological challenges surrounding them, therefore dramatically inhibiting the potential applications of ESC in basic biomedical studies and clinical medicine. Induced pluripotent stem cells (iPSCs), generated from the reprogrammed somatic cells, share similar characteristics including but not limited to the morphology and growth of ESC, self-renewal, and potential differentiation into various cell types. The discovery of the iPSC, unhindered by the aforementioned limitations of ESC, introduces a viable alternative to ESC. More importantly, the applications of iPSC in the development of disease models such as neurodegenerative disorders greatly enhance our understanding of the pathogenesis of such diseases and also facilitate the development of clinical therapeutic strategies using iPSC generated from patient somatic cells to avoid an immune rejection. In this review, we highlight the advances in iPSCs generation methods as well as the mechanisms behind their reprogramming. We also discuss future perspectives for the development of iPSC generation methods with higher efficiency and safety.
    Full-text · Article · Jan 2016 · Stem cell International
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    • "The discovery that transcription factors (TFs) can convert somatic cells into both specialized and induced pluripotent stem cells (iPSCs) has revolutionized stem cell research and promises to have major clinical applications (Graf and Enver, 2009; Yamanaka and Blau, 2010). Lineage-instructive TFs activate and repress tissue-specific genes by recognizing sequence-specific DNA consensus motifs contained within enhancers and promoters (Ptashne, 2007). "
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    ABSTRACT: Transcription-factor-induced somatic cell conversions are highly relevant for both basic and clinical research yet their mechanism is not fully understood and it is unclear whether they reflect normal differentiation processes. Here we show that during pre-B-cell-to-macrophage transdifferentiation, C/EBPα binds to two types of myeloid enhancers in B cells: pre-existing enhancers that are bound by PU.1, providing a platform for incoming C/EBPα; and de novo enhancers that are targeted by C/EBPα, acting as a pioneer factor for subsequent binding by PU.1. The order of factor binding dictates the upregulation kinetics of nearby genes. Pre-existing enhancers are broadly active throughout the hematopoietic lineage tree, including B cells. In contrast, de novo enhancers are silent in most cell types except in myeloid cells where they become activated by C/EBP factors. Our data suggest that C/EBPα recapitulates physiological developmental processes by short-circuiting two macrophage enhancer pathways in pre-B cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Stem Cell Reports
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    • "The TH2a/TH2b variants induce an open chromatin structure, and are enriched, and uniformly distributed both on the X chromosomes and autosomes [1]. Chromatin decondensation is a hallmark of reprogramming [10] [11]. Somatic cells can be experimentally reprogrammed back to pluripotency by nuclear transfer into oocytes [12], fusion with embryonic stem (ES) cells [13] or artificially overexpressing four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc (OSKM) [14]. "
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    ABSTRACT: Histone variants TH2a and TH2b are highly expressed in testes, oocytes and zygotes. Our recent analysis suggested that these histone variants enhance the induced generation of pluripotent stem cells (iPSCs) when co-expressed along with four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc (OSKM), and are associated with an open chromatin structure [1]. In the present study, we report the crystal structures of nucleosomes (NCPs) with the mouse histone variants, TH2a and TH2b. The structures revealed two significant changes, as compared to the canonical counterparts: fewer histone-DNA contacts and changes in dimer-dimer interactions between TH2a-TH2a' (L1-loop). In vivo studies with domain swapping and point mutants of the variants revealed that the residues in the histone tails and the TH2a-L1 loop are important for reprogramming. Taken together, our work indicates that the NCP variants with structural modifications and flexible tails are most likely important for enhanced reprogramming of functions. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Biochemical and Biophysical Research Communications
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