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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. S tem  C ells   2013;31:1737‐1748

Hypoxia induces re‐entry of committed cells into pluripotency