Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition

J Cell Biochem. 2011 Mar;112(3):804-17. doi: 10.1002/jcb.22961.


Cell therapy with bone marrow multipotential stromal cells (MSCs) represents a promising approach to promote wound healing and tissue regeneration. MSCs expanded in vitro lose early progenitors with differentiation and therapeutic potentials under normoxic condition, whereas hypoxic condition promotes MSC self-renewal through preserving colony forming early progenitors and maintaining undifferentiated phenotypes. Hypoxia inducible factor (HIF) pathway is a crucial signaling pathway activated in hypoxic condition. We evaluated the roles of HIFs in MSC differentiation, colony formation, and paracrine activity under hypoxic condition. Hypoxic condition reversibly decreased osteogenic and adipogenic differentiation. Decrease of osteogenic differentiation depended on HIF pathway; whereas decrease of adipogenic differentiation depended on the activation of unfolded protein response (UPR), but not HIFs. Hypoxia-mediated increase of MSC colony formation was not HIF-dependent also. Hypoxic exposure increased secretion of VEGF, HGF, and basic FGF in a HIF-dependent manner. These findings suggest that HIF has a limited, but pivotal role in enhancing MSC self-renewal and growth factor secretions under hypoxic condition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Aryl Hydrocarbon Receptor Nuclear Translocator / biosynthesis
  • Aryl Hydrocarbon Receptor Nuclear Translocator / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Cell Culture Techniques
  • Cell Differentiation / drug effects
  • Cell Hypoxia
  • Genes, Reporter
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Mesenchymal Stem Cells / cytology*
  • Osteocytes / cytology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phenylbutyrates / pharmacology
  • RNA Interference
  • RNA, Messenger / metabolism
  • Response Elements
  • Unfolded Protein Response


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PPAR gamma
  • Phenylbutyrates
  • RNA, Messenger
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • endothelial PAS domain-containing protein 1
  • 4-phenylbutyric acid