The Role of SMAD4 in Human Embryonic Stem Cell Self-Renewal and Stem Cell Fate

被引：34
作者：
Avery, Stuart [1 ,2 ]
Zafarana, Gaetano [2 ,3 ]
Gokhale, Paul J. [2 ]
Andrews, Peter W. [2 ]
机构：
[1] ASTAR, Inst Med Biol, Singapore 138648, Singapore
[2] Univ Sheffield, Ctr Stem Cell Biol, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England
[3] Univ Hlth Network, Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M5G 2M9, Canada
来源：
STEM CELLS | 2010年 / 28卷 / 05期
基金：
英国生物技术与生命科学研究理事会;
关键词：
Embryonic stem cell; Pluripotency; Self-renewal; SMAD4; Transforming growth factor-beta; Signaling; MAINTAINS PLURIPOTENCY; DEFINITIVE ENDODERM; DEFINED CONDITIONS; HUMAN BLASTOCYSTS; NEURAL INDUCTION; MOUSE EMBRYO; IN-VITRO; DIFFERENTIATION; NANOG; EXPRESSION;
D O I：
10.1002/stem.409
中图分类号：
Q813 [细胞工程];
学科分类号：
摘要：
Transforming growth factor (TGF)-beta superfamily proteins play a key role in the regulation of human embryonic stem cells (hESCs). Those of the TGF beta/activin/nodal branch seem to support self-renewal and pluripotency, whereas those of the bone morphogenic protein (BMP) branch induce differentiation. In contrast to this generalization, we found that hESC remained undifferentiated after knockdown of SMAD4 with inducible short hairpin RNA interference, although the knockdown inhibited TGF beta signaling and rendered the cells nonresponsive to BMP-induced differentiation. Moreover, the rapid differentiation of hESC after pharmacological inhibition of TGF beta/activin/nodal receptor signaling was restricted after SMAD4 knockdown. These results suggest that TGF beta/activin/nodal signaling supports the undifferentiated phenotype of hESC by suppressing BMP activity. During long-term culture, SMAD4 knockdown cell populations became less stable and more permissive to neural induction, a situation that was rescued by re-establishment of SMAD4 expression. These results suggest that SMAD4 is not required for maintenance of the undifferentiated state of hESC, but rather to stabilize that state. STEM CELLS 2010; 28: 863-873
引用
收藏
页码：863 / 873
页数：11
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