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Stem Cells. 2013 Sep;31(9):1737-48. doi: 10.1002/stem.1446.

Hypoxia induces re-entry of committed cells into pluripotency.

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Department of Biochemistry, University of Washington, Seattle, Washington, USA; Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA.


Adult stem cells reside in hypoxic niches, and embryonic stem cells (ESCs) are derived from a low oxygen environment. However, it is not clear whether hypoxia is critical for stem cell fate since for example human ESCs (hESCs) are able to self-renew in atmospheric oxygen concentrations as well. We now show that hypoxia can govern cell fate decisions since hypoxia alone can revert hESC- or iPSC-derived differentiated cells back to a stem cell-like state, as evidenced by re-activation of an Oct4-promoter reporter. Hypoxia-induced "de-differentiated" cells also mimic hESCs in their morphology, long-term self-renewal capacity, genome-wide mRNA and miRNA profiles, Oct4 promoter methylation state, cell surface markers TRA1-60 and SSEA4 expression, and capacity to form teratomas. These data demonstrate that hypoxia can influence cell fate decisions and could elucidate hypoxic niche function.


Human embryonic stem cell; Hypoxia; Plasticity; Stem cell fate; dedifferentiation; hESC; niche

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