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Article first published online: 24 JUL 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 8, pages 1685–1695, August 2012
How to Cite
Das, B., Bayat-Mokhtari, R., Tsui, M., Lotfi, S., Tsuchida, R., Felsher, D. W. and Yeger, H. (2012), HIF-2α Suppresses p53 to Enhance the Stemness and Regenerative Potential of Human Embryonic Stem Cells. STEM CELLS, 30: 1685–1695. doi: 10.1002/stem.1142
Author contributions: B.D.: conceived the idea, initiated the study, designed the experimental strategies, and wrote the manuscript; B.D., R.B.M., M.T., and S.L.: performed the in vitro and in vivo experiments; B.D., R.T., D.W.F., and H.Y.: analyzed the data and participated in manuscript revision.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS June 11, 2012; available online without subscription through the open access option.
- Issue published online: 24 JUL 2012
- Article first published online: 24 JUL 2012
- Accepted manuscript online: 11 JUN 2012 08:40AM EST
- Manuscript Accepted: 4 MAY 2012
- Manuscript Received: 29 NOV 2011
- Canadian Cancer Society Research Institute
- Grand Challenges Exploration Initiative grant
- Bill and Melinda Gates Foundation
- Laurel Foundation, CA
- Restracomp, Sick Kids Foundation, Hospital for Sick Children
- James Birrell Neuroblastoma Fund
- Embryonic stem cells;
- Neoplastic stem cell biology;
- Oxidative stress
Human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity in the area of tissue injury. However, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of hESCs. Here we report that when exposed to hypoxia/oxidative stress, a small fraction of hESCs, namely the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high hypoxia inducible factor (HIF)-2α state of transcriptional activity. This state can be sustained for a period of 2 weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, concomitant with high teratomagenic potential. Conditioned medium obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection both in vitro and in vivo. We termed this phenotype as the “enhanced stemness” state. We then demonstrated that the underlying molecular mechanism of this transient phenotype of enhanced stemness involved high Bcl-2, fibroblast growth factor (FGF)-2, and MDM2 expression and an altered state of the p53/MDM2 oscillation system. Specific silencing of HIF-2α and p53 resisted the reprogramming of SSEA3+/ABCG2+ to the enhanced stemness phenotype. Thus, our studies have uncovered a unique transient reprogramming activity in hESCs, the enhanced stemness reprogramming where a highly cytoprotective and undifferentiated state is achieved by transiently suppressing p53 activity. We suggest that this transient reprogramming is a form of stem cell altruism that benefits the surrounding tissues during the process of tissue regeneration. STEM CELLS2012;30:1685–1695