Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions.
Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions.
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DOI：
10.1083/jcb.201006094
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发表时间：
2010-11-01
期刊：
影响因子：
--
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Li D;Zhou J;Wang L;Shin ME;Su P;Lei X;Kuang H;Guo W;Yang H;Cheng L;Tanaka TS;Leckband DE;Reynolds AB;Duan E;Wang F
非肌肉肌球蛋白IIA和p120-catenin控制E-cadherin介导的细胞-细胞粘附，对hESC多能性和长期存活至关重要人胚胎干细胞（ESC [hESC]）作为集落增殖，其中单个细胞彼此强烈粘附。这种结构与人胚胎干细胞的自我更新、多能性和存活有关，并依赖于上皮钙粘蛋白（E-钙粘蛋白）、NMMIIA（非肌肉肌球蛋白IIA）和p120-连环蛋白。E-cadherin和p120-catenin在一个正反馈环中起作用，促进E-cadherin在细胞间连接处的局部积累。NMMIIA稳定p120-catenin蛋白并控制E-钙粘蛋白介导的细胞间粘附。该信号网络的扰动破坏集落形成，使多能性的转录调控回路不稳定，并损害hESC的长期存活。此外，E-钙粘蛋白的耗尽显著降低了将人类体细胞重编程为ESC样状态的效率。反馈调节和机械-生化整合为hESC在长期自我更新过程中的细胞间粘附和细胞结构的调节提供了机制见解。我们的研究结果也有助于理解hESC身份和体细胞重编程的微环境调控。
Nonmuscle myosin IIA and p120-catenin control E-cadherin–mediated cell–cell adhesions essential for hESC pluripotency and long-term survival. Human embryonic stem cells (ESCs [hESCs]) proliferate as colonies wherein individual cells are strongly adhered to one another. This architecture is linked to hESC self-renewal, pluripotency, and survival and depends on epithelial cadherin (E-cadherin), NMMIIA (nonmuscle myosin IIA), and p120-catenin. E-cadherin and p120-catenin work within a positive feedback loop that promotes localized accumulation of E-cadherin at intercellular junctions. NMMIIA stabilizes p120-catenin protein and controls E-cadherin–mediated intercellular adhesion. Perturbations of this signaling network disrupt colony formation, destabilize the transcriptional regulatory circuitry for pluripotency, and impair long-term survival of hESCs. Furthermore, depletion of E-cadherin markedly reduces the efficiency of reprogramming of human somatic cells to an ESC-like state. The feedback regulation and mechanical–biochemical integration provide mechanistic insights for the regulation of intercellular adhesion and cellular architecture in hESCs during long-term self-renewal. Our findings also contribute to the understanding of microenvironmental regulation of hESC identity and somatic reprogramming.
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