Journal
STEM CELLS
Volume 27, Issue 9, Pages 2069-2080Publisher
WILEY
DOI: 10.1002/stem.134
Keywords
E-cadherin; Embryonic stem cells; beta-catenin; Activin; FGF; Nodal
Categories
Funding
- Association for International Cancer Research
- Biotechnology and Biological Sciences Research Council
- Royal Society
- Technology Strategy Board
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council [BB/E527239/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [TS/G000646/1] Funding Source: researchfish
- BBSRC [BB/E527239/1] Funding Source: UKRI
- EPSRC [TS/G000646/1] Funding Source: UKRI
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We have previously demonstrated that differentiation of embryonic stem (ES) cells is associated with downregulation of cell surface E-cadherin. In this study, we assessed the function of E-cadherin in mouse ES cell pluripotency and differentiation. We show that inhibition of E-cadherin-mediated cell-cell contact in ES cells using gene knockout (Ecad(-/-)), RNA interference (EcadRNAi), or a transhomodimerization-inhibiting peptide (CHAVC) results in cellular proliferation and maintenance of an undifferentiated phenotype in fetal bovine serum-supplemented medium in the absence of leukemia inhibitory factor (LIF). Re-expression of E-cadherin in Ecad(-/-), EcadRNAi, and CHAVC-treated ES cells restores cellular dependence to LIF supplementation. Although reversal of the LIF-independent phenotype in Ecad(-/-) ES cells is dependent on the beta-catenin binding domain of E-cadherin, we show that beta-catenin null (beta cat(-/-)) ES cells also remain undifferentiated in the absence of LIF. This suggests that LIF-independent self-renewal of Ecad(-/-) ES cells is unlikely to be via beta-catenin signaling. Exposure of Ecad(-/-), EcadRNAi, and CHAVC-treated ES cells to the activin receptor-like kinase inhibitor SB431542 led to differentiation of the cells, which could be prevented by re-expression of E-cadherin. To confirm the role of transforming growth factor beta family signaling in the self-renewal of Ecad(-/-) ES cells, we show that these cells maintain an undifferentiated phenotype when cultured in serum-free medium supplemented with Activin A and Nodal, with fibroblast growth factor 2 required for cellular proliferation. We conclude that transhomodimerization of E-cadherin protein is required for LIF-dependent ES cell self-renewal and that multiple self-renewal signaling networks subsist in ES cells, with activity dependent upon the cellular context. STEM CELLS 2009; 27: 2069-2080
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