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Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules.

ABSTRACT: 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.

SUBMITTER: Xu Y

PROVIDER: S-EPMC2889586 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules.

Xu Yue Y Zhu Xiuwen X Hahm Heung Sik HS Wei Wanguo W Hao Ergeng E Hayek Alberto A Ding Sheng S

Proceedings of the National Academy of Sciences of the United States of America 20100420 18

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 foun ...[more]

PMID: 20406903

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Project description:Embryonic stem cell (ESC) self-renewal and pluripotency is controlled by the coordinated action of transcription factors and chromatin regulators. Compared to the pluripotency transcription factors, the function of the chromatin regulators, especially the ATP-dependent chromatin remodelers, remains poorly understood in ESCs. Here, we show that INO80, a SWI/SNF family chromatin remodeling complex, is essential for ESC self-renewal, pluripotency, somatic cell reprogramming, and embryonic development. Ino80, the ATPase of the complex, forms an auto-regulatory loop with the ESC master transcription factors Oct4, Nanog, and Sox2. More importantly, it co-occupies the enhancer regions of most key pluripotency genes with the master transcription factors, and positively regulates their expression by maintaining an open chromatin structure. Our data suggests that INO80 is an integral component of the pluripotency transcription network, and plays a critical role in both the maintenance and establishment of pluripotency Mouse J1 cells were infected with lentiviral-shNT or lentiviral-Ino80, RNA was extracted at 2, 4 or 6 days after infection. agent: non-targeting shRNA: NS_Day_2_1, NS_Day_2_2, NS_Day_4_1, NS_Day_4_2, NS_Day_6_1, NS_Day_6_2 agent: Ino80 shRNA: shIno80_Day_2_1, shIno80_Day_2_2, shIno80_Day_4_1, shIno80_Day_4_2, shIno80_Day_6_1, shIno80_Day_6_2 time: 48 hours: NS_Day_2_1, NS_Day_2_2, shIno80_Day_2_1, shIno80_Day_2_2 time: 96 hours: NS_Day_4_1, NS_Day_4_2, shIno80_Day_4_1, shIno80_Day_4_2 time: 144 hours: NS_Day_6_1, NS_Day_6_2, shIno80_Day_6_1, shIno80_Day_6_2 cell line: mouse J1 ESC: NS_Day_2_1, NS_Day_2_2, shIno80_Day_2_1, shIno80_Day_2_2, NS_Day_4_1, NS_Day_4_2, shIno80_Day_4_1, shIno80_Day_4_2, NS_Day_6_1, NS_Day_6_2, shIno80_Day_6_1, shIno80_Day_6_2 biological replicate: shIno80_Day_2_1, shIno80_Day_2_2 biological replicate: shIno80_Day_4_1, shIno80_Day_4_2 biological replicate: shIno80_Day_6_1, shIno80_Day_6_2 biological replicate: NS_Day_2_1, NS_Day_2_2 biological replicate: NS_Day_4_1, NS_Day_4_2 biological replicate: NS_Day_6_1, NS_Day_6_2

Dataset Information

Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules.

Publications

Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules.

Similar Datasets

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