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ZFX 控制人类胚胎干细胞的自我更新。

ZFX controls the self-renewal of human embryonic stem cells.

机构信息

Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America.

出版信息

PLoS One. 2012;7(8):e42302. doi: 10.1371/journal.pone.0042302. Epub 2012 Aug 3.

DOI:10.1371/journal.pone.0042302
PMID:22879936
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3411758/
Abstract

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) offer great promise in regenerative medicine and disease modeling due to their unlimited self-renewal and broad differentiation capacity. There is evidence that the growth properties and critical signaling pathways differ between murine and human ESCs; therefore, it is essential to perform functional studies to test the putatively conserved mechanisms of pluripotent stem cell self-renewal between species. Previously, we identified the transcription factor Zfx as a key regulator of self-renewal in murine ESCs. Here we extend those findings to human ESCs. ZFX knockdown in hESCs hindered clonal growth and decreased colony size after serial replating. ZFX overexpression enhanced clone formation in the presence of Y-27632, increased colony size at low density and decreased expression of differentiation-related genes in human ESCs. ZFX-overexpressing hESCs resisted spontaneous differentiation but could be directed to differentiate into endodermal and neural cell fates when provided with the appropriate cues. Thus, ZFX acts as a molecular rheostat regulating the balance between self-renewal and differentiation in hESCs, revealing the close evolutionary conservation of the self-renewal mechanisms in murine and human ESCs.

摘要

胚胎干细胞 (ESCs) 和诱导多能干细胞 (iPSCs) 由于其无限的自我更新和广泛的分化能力，在再生医学和疾病建模方面具有巨大的应用前景。有证据表明，鼠类和人类 ESCs 的生长特性和关键信号通路存在差异；因此，进行功能研究以测试物种间多能干细胞自我更新的假定保守机制至关重要。此前，我们发现转录因子 Zfx 是鼠类 ESCs 自我更新的关键调节因子。在这里，我们将这些发现扩展到人类 ESCs。在 hESCs 中敲低 ZFX 会阻碍克隆生长，并在连续传代后降低集落大小。ZFX 过表达在 Y-27632 存在的情况下增强克隆形成，在低密度时增加集落大小，并降低人类 ESCs 中分化相关基因的表达。ZFX 过表达的 hESCs 抵抗自发分化，但当提供适当的信号时，可以被诱导分化为内胚层和神经细胞命运。因此，ZFX 作为一种分子变阻器，调节 hESCs 中自我更新和分化之间的平衡，揭示了鼠类和人类 ESCs 自我更新机制的密切进化保守性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/2085ffb2a56b/pone.0042302.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/e2b72b5104d2/pone.0042302.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/687ccf49c9f1/pone.0042302.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/d913e5618e1e/pone.0042302.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/79c395b0c236/pone.0042302.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/a9413c444426/pone.0042302.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/2085ffb2a56b/pone.0042302.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/e2b72b5104d2/pone.0042302.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/687ccf49c9f1/pone.0042302.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/d913e5618e1e/pone.0042302.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/79c395b0c236/pone.0042302.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/a9413c444426/pone.0042302.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d950/3411758/2085ffb2a56b/pone.0042302.g006.jpg

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