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Embryonic Stem Cells/Induced Pluripotent Stem Cells
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A Unique Interplay Between Rap1 and E-Cadherin in the Endocytic Pathway Regulates Self-Renewal of Human Embryonic Stem Cells†‡§
Article first published online: 28 DEC 2009
DOI: 10.1002/stem.289
Copyright © 2010 AlphaMed Press
Additional Information
How to Cite
Li, L., Wang, S., Jezierski, A., Moalim-Nour, L., Mohib, K., Parks, R. J., Francesco Retta, S. and Wang, L. (2010), A Unique Interplay Between Rap1 and E-Cadherin in the Endocytic Pathway Regulates Self-Renewal of Human Embryonic Stem Cells. STEM CELLS, 28: 247–257. doi: 10.1002/stem.289
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Author contributions: L.L.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; S.W. and A.J.: collection and assembly of data, data analysis and interpretation; L.M.-N. and K.M.: collection of data; R.J.P. and S.F.R.: provision of study material, data interpretation, manuscript writing; L.W.: conception and design, data interpretation, manuscript writing, financial support, final approval of manuscript. L.L., S.W., and A.J. contributed equally to this work.
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Disclosure of potential conflicts of interest is found at the end of this article.
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First published online in STEM CELLSEXPRESS January 28, 2010.
Publication History
- Issue published online: 16 FEB 2010
- Article first published online: 28 DEC 2009
- Accepted manuscript online: 28 DEC 2009 12:00AM EST
- Manuscript Accepted: 12 DEC 2009
- Manuscript Received: 9 JUL 2009
Funded by
- Canadian Institutes of Health Research (CIHR). Grant Number: MOP-158235
- CIHR New Investigator Award. Grant Number: MSH-166732
- Ontario Genomics Institute. Grant Number: 2008-OGI-TD-01
- Fondazione Telethon. Grant Number: GGP06222
- CIHR Frederick Banting and Charles Best Canada Graduate Scholarship award
- Fellowship of Canadian Blood Services
Keywords:
- Rap1;
- E-cadherin;
- Human embryonic stem cells;
- Endocytic pathway;
- Self-renewal;
- Differentiation
Abstract
Regulatory mechanisms pertaining to the self-renewal of stem cells remain incompletely understood. Here, we show that functional interactions between small GTPase Rap1 and the adhesion molecule E-cadherin uniquely regulate the self-renewal of human embryonic stem cells (hESCs). Inhibition of Rap1 suppresses colony formation and self-renewal of hESCs, whereas overexpression of Rap1 augments hESC clonogenicity. Rap1 does not directly influence the expression of the pluripotency genes Oct4 and Nanog. Instead, it affects the endocytic recycling pathway involved in the formation and maintenance of E-cadherin-mediated cell–cell cohesion, which is essential for the colony formation and self-renewal of hESCs. Conversely, distinct from epithelial cells, disruption of E-cadherin mediated cell–cell adhesions induces lysosome delivery and degradation of Rap1. This in turn leads to a further downregulation of E-cadherin function and a subsequent reduction in hESC clonogenic capacity. These findings provide the first demonstration that the interplay between Rap1 and E-cadherin along the endocytic recycling pathway serves as a timely and efficient mechanism to regulate hESC self-renewal. Given the availability of specific activators for Rap1, this work provides a new perspective to enable better maintenance of human pluripotent stem cells. STEM CELLS 2010;28:247–257