Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells
Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells
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DOI：
10.1002/stem.607
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发表时间：
2011-04-01
期刊：
影响因子：
5.2
通讯作者：
Sommer, Lukas
中科院分区：
文献类型：
--
作者：
John, Nessy;Cinelli, Paolo;Sommer, Lukas
在脊椎动物发育过程中，神经嵴干细胞（NCSCs）产生周围神经系统的神经细胞和各种间充质细胞类型，包括平滑肌细胞、颅面软骨细胞和骨细胞。尽管间充质干细胞（MSCs）产生的机制仍有待确定，但最近的研究表明，间充质干细胞（MSCs）部分来源于神经嵴（NC）。在这里，我们发现转化生长因子β (TGF β)介导的NCSC转录因子Sox10的抑制诱导了NCSC神经到间充质电位的转换。在体外和体内，TGF β信号失活导致Sox10持续表达，细胞周期退出减少，间充质衍生物生成紊乱，最终导致形态发生缺陷。而TGF - β介导的Sox10下调或基因失活，在体外抑制神经电位，赋予NC细胞间充质电位，在体内促进细胞周期退出和间充质早熟分化。因此，TGF β信号对Sox10的负调控促进了NCSCs间充质祖细胞的产生。我们的研究可能为未来的应用奠定基础，这些应用需要明确的MSCs群体用于再生医学。干细胞2011；29日:689 - 699
During vertebrate development, neural crest stem cells (NCSCs) give rise to neural cells of the peripheral nervous system and to a variety of mesenchymal cell types, including smooth muscle, craniofacial chondrocytes, and osteocytes. Consistently, mesenchymal stem cells (MSCs) have recently been shown to derive in part from the neural crest (NC), although the mechanisms underlying MSC generation remains to be identified. Here, we show that transforming growth factor beta (TGF beta)-mediated suppression of the NCSC transcription factor Sox10 induces a switch in neural to mesenchymal potential in NCSCs. In vitro and in vivo, TGF beta signal inactivation results in persistent Sox10 expression, decreased cell cycle exit, and perturbed generation of mesenchymal derivatives, which eventually leads to defective morphogenesis. In contrast, TGF beta-mediated downregulation of Sox10 or its genetic inactivation suppresses neural potential, confers mesenchymal potential to NC cells in vitro, and promotes cell cycle exit and precocious mesenchymal differentiation in vivo. Thus, negative regulation of Sox10 by TGF beta signaling promotes the generation of mesenchymal progenitors from NCSCs. Our study might lay the grounds for future applications demanding defined populations of MSCs for regenerative medicine. STEM CELLS 2011; 29: 689-699