Non-hypoxic pharmacological stabilisation of Hypoxia Inducible Factor 1α: effects on dopaminergic differentiation of human neural stem cells.

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Non-hypoxic pharmacological stabilisation of Hypoxia Inducible Factor 1α: effects on dopaminergic differentiation of human neural stem cells.

Eur J Neurosci. 2018 Nov 24;:

Authors: Hey SM, Jensen P, Ryding M, Martínez-Serrano A, Kristensen BW, Meyer M

Abstract
Parkinson's disease is a neurodegenerative disease resulting in degeneration of midbrain dopaminergic neurons. Exploratory studies using human fetal 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). Stabilisation 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 non-competitive (FG-0041) and competitive (Compound A and JNJ-42041935) HIF-1α stabilising compounds on the dopaminergic differentiation of human neural stem cells. Treatment with all HPH inhibitors at high oxygen tension (20%) resulted in HIF-1α stabilisation 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 stabilisation, the cultures displayed a slightly reduced proliferative activity and significantly increased relative levels of tyrosine hydroxylase-positive dopaminergic neurons. In conclusion, HIF-1α stabilisation may represent a promising strategy for the generation of dopaminergic neurons intended for use in experimental in vitro studies and cell replacement therapies. This article is protected by copyright. All rights reserved.

PMID: 30471165 [PubMed - as supplied by publisher]

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