Cell Stem Cell：化学小分子可替代基因诱导iPS细胞

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Cell Stem Cell：化学小分子可替代基因诱导iPS细胞& F% Q. Y0 n" g) K9 r2 w! w
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近日，哈佛大学干细胞研究所(HSCI)的科学家研究诱导的多能干细胞取得进步。该研究报告发表在10月8日Cell Stem Cell杂志网络版上。
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8 {1 h. c3 x/ V' Y5 e& \- g. P目前的iPS细胞研究中，将成人的皮肤细胞重编程转化为胚胎干细胞状态一般需要四个基因参与。该课题组利用一种小分子化学物质RepSox代替了其中的Sox2和  cMyc基因的功能，并且RepSox是在该实验的不同时间以不同的形式发挥功能。由于cMyc是肿瘤促进因子(tumor promoter)，利用  cMyc产生的iPS细胞不能用于人类疾病治疗，因此十分有必要寻找一种不使用cMyc基因的产生iPS细胞新方法。3 U0 Q( t# @' ^% i9 I2 Y) m$ q

/ r, T; K+ ]  @! O7 |. j找到一种安全生产iPS细胞的方法与研究胚胎干细胞具有同等重要的生物学意义。因为以患者自身细胞重编程产生的细胞在移植后理论上可以不需要使用免疫抑制药物。同样的，患者特异性的iPS细胞还能用于治疗心脏损伤或其他个性化的治疗中。/ k! }9 L5 b- i/ b& x

: A. G- {2 J, N7 _! F5 a第一作者Justin K. Ichida介绍说，这项发现证实了利用某些化学药物针对某些需要做移植手术的患者产生更安全的干细胞的可行性( j5 F8 U8 v. x' R  w
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8 g$ }% Q! s0 L7 w9 SCell Stem Cell, 08 October 2009 doi:10.1016/j.stem.2009.09.012
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8 a/ l* T5 d- f) v" r  kA Small-Molecule Inhibitor of Tgf-β Signaling Replaces Sox2 in Reprogramming by Inducing Nanog
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Justin K. Ichida1, 3, 6, Joel Blanchard1, 6, Kelvin Lam1, 6, Esther Y. Son1, 2, 3, 5, 6, Julia E. Chung1, 2, 3, Dieter Egli1, 3, Kyle M. Loh1, Ava C. Carter1, 3, Francesco P. Di Giorgio1, 3, Kathryn Koszka1, 3, Danwei Huangfu1, Hidenori Akutsu4, David R. Liu5, Lee L. Rubin1, ,   and Kevin Eggan1, 2, 3, ,  ; }- C# e! g( t* R& ^+ a
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1 Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
) F' J% h" O1 A0 S( n0 n2 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA
5 g& z0 z, z% A- @$ c- |3 Stowers Medical Institute, 1000 East 50th Street. Kansas City, MO 64110, USA
2 D$ I* M# J5 @# E% `4 Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535" }! d2 H  X! {$ j9 K
5 Howard Hughes Medical Institute and the Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
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The combined activity of three transcription factors can reprogram adult cells into induced pluripotent stem cells (iPSCs). However, the transgenic methods used for delivering reprogramming factors have raised concerns regarding the future utility of the resulting stem cells. These uncertainties could be overcome if each transgenic factor were replaced with a small molecule that either directly activated its expression from the somatic genome or in some way compensated for its activity. To this end, we have used high-content chemical screening to identify small molecules that can replace Sox2 in reprogramming. We show that one of these molecules functions in reprogramming by inhibiting Tgf-β signaling in a stable and trapped intermediate cell type that forms during the process. We find that this inhibition promotes the completion of reprogramming through induction of the transcription factor Nanog.