Non-hypoxic stabilization of hypoxia-inducible factor alpha (HIF-alpha): relevance in neural progenitor/stem cells

Neurotox Res. 2009 May;15(4):367-80. doi: 10.1007/s12640-009-9043-z. Epub 2009 Mar 20.

Abstract

Hypoxia-inducible factor-1 (HIF-1) plays an important role in neural progenitor cell (NPC) propagation and dopaminergic differentiation. In the presence of oxygen and iron, hypoxia-inducible factor 1 alpha (HIF-1alpha) is rapidly degraded via the prolyl hydroxylase (PHD)/VHL pathway. In addition to hypoxia, various non-hypoxic stimuli can stabilize HIF-1alpha in NPCs and influence the transcription of HIF-regulated genes. Here, we investigate various hypoxia mimetics: deferoxamine (DFO), ciclopirox olamine (CPX), dimethyloxallyl glycine (DMOG), a novel HIF-PHD inhibitor (FG-4497) and cobalt chloride (CoCl(2)) with respect to their ability to enhance in vitro proliferation, neurogenesis and dopaminergic differentiation of human fetal mesencephalic NPCs (hmNPCs) in ambient oxygen (21%). Although able to stabilize HIF-1alpha, iron chelators (DFO and CPX) and DMOG were toxic to hmNPCs. CoCl(2) was beneficial only towards neuronal and dopaminergic differentiation, while FG-4497 enhanced proliferation, neurogenesis and dopaminergic differentiation of hmNPCs. Both CoCl(2) and FG-4497 were protective to human dopaminergic neurons. Finally, exposure to hyperbaric oxygen (HBO) also stabilized HIF-1alpha in hmNPCs and induced neurogenesis in vitro. These findings suggest that several HIF stabilizing agents or conditions can rescue impaired neurons and promote neurogenesis in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Analysis of Variance
  • Antifungal Agents / pharmacology
  • Cell Cycle / drug effects
  • Cell Death / drug effects
  • Cell Differentiation / drug effects*
  • Cell Line, Transformed
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Ciclopirox
  • Cobalt / pharmacology
  • Deferoxamine / pharmacology
  • Dose-Response Relationship, Drug
  • Embryonic Stem Cells / drug effects*
  • Fetus
  • Humans
  • Hyperbaric Oxygenation / methods
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / pharmacology*
  • Mesencephalon / cytology
  • Nerve Tissue Proteins / metabolism
  • Pyridones / pharmacology
  • Siderophores / pharmacology

Substances

  • Actins
  • Antifungal Agents
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nerve Tissue Proteins
  • Pyridones
  • Siderophores
  • Ciclopirox
  • Cobalt
  • cobaltous chloride
  • Deferoxamine