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01.05.2009

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

verfasst von: Javorina Milosevic, Irena Adler, Anatol Manaenko, Sigrid C. Schwarz, Gail Walkinshaw, Michael Arend, Lee A. Flippin, Alexander Storch, Johannes Schwarz

Erschienen in: Neurotoxicity Research | Ausgabe 4/2009

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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-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 (CoCl₂) 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. CoCl₂ was beneficial only towards neuronal and dopaminergic differentiation, while FG-4497 enhanced proliferation, neurogenesis and dopaminergic differentiation of hmNPCs. Both CoCl₂ 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.

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Titel: Non-hypoxic Stabilization of Hypoxia-Inducible Factor Alpha (HIF-α): Relevance in Neural Progenitor/Stem Cells
verfasst von: Javorina Milosevic
Irena Adler
Anatol Manaenko
Sigrid C. Schwarz
Gail Walkinshaw
Michael Arend
Lee A. Flippin
Alexander Storch
Johannes Schwarz
Publikationsdatum: 01.05.2009
Verlag: Springer-Verlag
Erschienen in: Neurotoxicity Research / Ausgabe 4/2009
Print ISSN: 1029-8428
Elektronische ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-009-9043-z

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