title: Non-hypoxic stabilization of hypoxia-inducible factor alpha (HIF-alpha): relevance in neural progenitor/stem cells.
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.
authors.affiliation: Translational Centre for Regenerative Medicine-Leipzig (TRM-Leipzig), University of Leipzig, Philipp-Rosenthal-Strasse 55, 04103, Leipzig, Germany. jmilosevic@trm.uni-leipzig.de
authors.forename: Javorina
authors.initials: J
authors.lastname: Milosevic
authors.forename: Irena
authors.initials: I
authors.lastname: Adler
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Schwarz
authors.forename: Gail
authors.initials: G
authors.lastname: Walkinshaw
authors.forename: Michael
authors.initials: M
authors.lastname: Arend
authors.forename: Lee A
authors.initials: LA
authors.lastname: Flippin
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.forename: Johannes
authors.initials: J
authors.lastname: Schwarz
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077768:Ciclopirox; D003035:Cobalt / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects*; D005333:Fetus; D006801:Humans; D006931:Hyperbaric Oxygenation / Q000379:methods; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D017262:Siderophores / Q000494:pharmacology
chemical_list: D000199:Actins; D000935:Antifungal Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D011728:Pyridones; D017262:Siderophores; D000077768:Ciclopirox; D003035:Cobalt; C018021:cobaltous chloride; D003676:Deferoxamine