Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules.
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.
Xu
Yue
Y
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Zhu
Xiuwen
X
Hahm
Heung Sik
HS
Wei
Wanguo
W
Hao
Ergeng
E
Hayek
Alberto
A
Ding
Sheng
S
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D048430:Cell Shape; D002470:Cell Survival; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
D015820:Cadherins; D016023:Integrins; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins
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