Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2010 May 4;107(18):8129-34. doi: 10.1073/pnas.1002024107. Epub 2010 Apr 20.
Using a high-throughput chemical screen, we identified two small molecules that enhance the survival of human embryonic stem cells (hESCs). By characterizing their mechanisms of action, we discovered an essential role of E-cadherin signaling for ESC survival. Specifically, we showed that the primary cause of hESC death following enzymatic dissociation comes from an irreparable disruption of E-cadherin signaling, which then leads to a fatal perturbation of integrin signaling. Furthermore, we found that stability of E-cadherin and the resulting survival of ESCs were controlled by specific growth factor signaling. Finally, we generated mESC-like hESCs by culturing them in mESC conditions. And these converted hESCs rely more on E-cadherin signaling and significantly less on integrin signaling. Our data suggest that differential usage of cell adhesion systems by ESCs to maintain self-renewal may explain their profound differences in terms of morphology, growth factor requirement, and sensitivity to enzymatic cell dissociation.
利用高通量化学筛选，我们鉴定出两种能提高人胚胎干细胞（hESC）存活率的小分子。通过对其作用机制进行表征，我们发现 E-钙黏蛋白信号对于 ESC 存活至关重要。具体而言，我们表明 hESC 在经过酶解分离后死亡的主要原因是 E-钙黏蛋白信号的不可修复破坏，进而导致整合素信号的致命干扰。此外，我们发现 E-钙黏蛋白的稳定性以及由此产生的 ESC 存活受到特定生长因子信号的控制。最后，我们通过在 mESC 条件下培养来生成类 mESC 的 hESC。并且这些转化后的 hESC 更依赖于 E-钙黏蛋白信号，而对整合素信号的依赖性显著降低。我们的数据表明，ESC 维持自我更新时对细胞黏附系统的不同使用可能解释了它们在形态、生长因子需求以及对酶解细胞分离的敏感性方面的显著差异。
