Non-hypoxic Stabilization of Hypoxia-Inducible Factor Alpha (HIF-α): Relevance in Neural Progenitor/Stem Cells

• Published in: Neurotoxicity research Vol. 15; no. 4; pp. 367 - 380
• Main Authors: Milosevic, Javorina, Adler, Irena, Manaenko, Anatol, Schwarz, Sigrid C., Walkinshaw, Gail, Arend, Michael, Flippin, Lee A., Storch, Alexander, Schwarz, Johannes
• Format: Journal Article
• Language: English
• Published: New York Springer-Verlag 01-05-2009
• Subjects: Actins - metabolism; Analysis of Variance; Antifungal Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Cycle - drug effects; Cell Death - drug effects; Cell Differentiation - drug effects; Cell Line, Transformed; Cell Proliferation - drug effects; Cell Survival - drug effects; 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; Neurobiology; Neurochemistry; Neurology; Neurosciences; Pharmacology/Toxicology; Pyridones - pharmacology; Siderophores - pharmacology; Neuroprotection; Hyperbaric oxygen (HBO); Non-hypoxia; Neural progenitor cells; Hypoxia; Hypoxia-inducible factor-1α (HIF-1α); Neurogenesis
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-009-9043-z

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-1α) is rapidly degraded via the prolyl hydroxylase (PHD)/VHL pathway. In addition to hypoxia, various non-hypoxic stimuli can stabilize HIF-1α 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-1α, 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-1α 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.