Nonhypoxic pharmacological stabilization of Hypoxia Inducible Factor 1α: Effects on dopaminergic differentiation of human neural stem cells.

Publisher: Wiley-Blackwell Country of Publication: France NLM ID: 8918110 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-9568 (Electronic) Linking ISSN: 0953816X NLM ISO Abbreviation: Eur J Neurosci Subsets: MEDLINE

Publication: : Oxford : Wiley-Blackwell
Original Publication: Oxford, UK : Published on behalf of the European Neuroscience Association by Oxford University Press, c1989-

Cell Differentiation/*drug effects ; Dopaminergic Neurons/*drug effects ; Hypoxia-Inducible Factor 1, alpha Subunit/*drug effects ; Neural Stem Cells/*drug effects ; Prolyl-Hydroxylase Inhibitors/*pharmacology; Benzimidazoles/pharmacology ; Cell Line ; Fetus ; Humans ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors ; Mesencephalon/cytology ; Parkinson Disease ; Phenanthrolines/pharmacology ; Pyrazoles/pharmacology

Parkinson's disease is a neurodegenerative disease resulting in degeneration of midbrain dopaminergic neurons. Exploratory studies using human foetal tissue or predifferentiated stem cells have suggested that intracerebral transplantation of dopaminergic precursor cells may become an effective treatment for patients with Parkinson's disease. However, strategies for dopaminergic stem cell differentiation vary widely in efficiency, and better methods still need to be developed. Hypoxia Inducible Factor 1 (HIF-1) is a transcription factor involved in the regulation of genes important for cellular adaption to hypoxia and low glucose supply. HIF-1 is to a large degree regulated by the availability of oxygen as in its presence, the subunit HIF-1α is degraded by HIF prolyl hydroxylase enzymes (HPHs). Stabilization of HIF-1α through inhibition of HPHs has been shown to increase dopaminergic differentiation of stem cells and to protect dopaminergic neurons against neurotoxins. This study investigated the effects of noncompetitive (FG-0041) and competitive (Compound A and JNJ-42041935) HIF-1α stabilizing compounds on the dopaminergic differentiation of human neural stem cells. Treatment with all HPH inhibitors at high oxygen tension (20%) resulted in HIF-1α stabilization as assessed by immunocytochemistry for HIF-1α and detection of increased levels of vascular endothelial growth factor in the conditioned culture medium. Following 10 days of HIF-1α stabilization, the cultures displayed a slightly reduced proliferative activity and significantly increased relative levels of tyrosine hydroxylase-positive dopaminergic neurons. In conclusion, HIF-1α stabilization may represent a promising strategy for the generation of dopaminergic neurons intended for use in experimental in vitro studies and cell replacement therapies.
(© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

International IMK Almene Fond; International The Danish Parkinson Foundation; FSS 12-132155 International Independent Research Fund Denmark

Keywords: HIF prolyl hydroxylase; HIF-1α; Parkinson's disease; oxygen tension; tyrosine hydroxylase

0 (1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid)
0 (Benzimidazoles)
0 (FG 0041)
0 (HIF1A protein, human)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (Phenanthrolines)
0 (Prolyl-Hydroxylase Inhibitors)
0 (Pyrazoles)
EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)

Date Created: 20181125 Date Completed: 20200622 Latest Revision: 20200622

20240105

10.1111/ejn.14284

30471165