title: Hypoxia induces re-entry of committed cells into pluripotency.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington, USA; Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, Washington, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Mathieu
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Angelique
authors.initials: A
authors.lastname: Nelson
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Lamba
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Reh
authors.forename: Carol
authors.initials: C
authors.lastname: Ware
authors.forename: Hannele
authors.initials: H
authors.lastname: Ruohola-Baker
mesh_terms: D000328:Adult; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D054337:Cell Dedifferentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D049452:Green Fluorescent Proteins; D006655:Histone Deacetylases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050814:Octamer Transcription Factor-3; D010100:Oxygen; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human
keywords: Human embryonic stem cell; Hypoxia; Plasticity; Stem cell fate; dedifferentiation; hESC; niche