title: Hypoxia induces pluripotency in primordial germ cells by HIF1α stabilization and Oct4 deregulation.
abstract: OBJECTIVE
  To study the mechanisms of pluripotency induction, we compared gene expression in pluripotent embryonic germ cells (EGCs) and unipotent primordial germ cells (PGCs).
  
  
  RESULTS
  We found 11 genes ≥1.5-fold overexpressed in EGCs. None of the genes identified was the Yamanaka genes but instead related to glycolytic metabolism. The prospect of pluripotency induction by cell metabolism manipulation was investigated by hypoxic culturing. Hypoxia induced a glycolytic program in PGCs in detriment of mitochondrial oxidative phosphorylation. We demonstrate that hypoxia alone induces reprogramming in PGCs, giving rise to hypoxia-induced EGC-like cells (hiEGLs), which differentiate into cells of the three germ layers in vitro and contribute to the internal cell mass of the blastocyst in vivo, demonstrating pluripotency. The mechanism of hypoxia induction involves HIF1α stabilization and Oct4 deregulation. However, hiEGL cannot be passaged long term. Self-renewal capacity is not achieved by hypoxia likely due to the lack of upregulation of c-Myc and Klf4. Gene expression analysis of hypoxia signaling suggests that hiEGLs have not reached the stabilization phase of cell reprogramming.
  
  
  CONCLUSIONS
  Our data suggest that the two main properties of stemness, pluripotency and self-renewal, are differentially regulated in PGC reprogramming induced by hypoxia.
authors.affiliation: 1 Cell Engineering Laboratory, IdiPaz, La Paz Hospital Research Institute , Madrid Spain .
authors.forename: Pilar
authors.initials: P
authors.lastname: López-Iglesias
authors.forename: Yago
authors.initials: Y
authors.lastname: Alcaina
authors.forename: Natalia
authors.initials: N
authors.lastname: Tapia
authors.forename: Davood
authors.initials: D
authors.lastname: Sabour
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Arauzo-Bravo
authors.forename: Diego
authors.initials: D
authors.lastname: Sainz de la Maza
authors.forename: Edurne
authors.initials: E
authors.lastname: Berra
authors.forename: Analia Nunez
authors.initials: AN
authors.lastname: O'Mara
authors.forename: Manuel
authors.initials: M
authors.lastname: Nistal
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Donovan
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.forename: Maria P
authors.initials: MP
authors.lastname: De Miguel
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005854:Germ Cells / Q000502:physiology*; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D039904:Pluripotent Stem Cells / Q000378:metabolism; D055550:Protein Stability; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse