Journal
CELL STEM CELL
Volume 28, Issue 2, Pages 257-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2020.09.019
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Funding
- National Institutes of Health [F30HD096784, T32NS077888, T32GM007250]
- New York Stem Cell Foundation
- Small Molecule Drug Development and Genomics core facilities of the CWRU Comprehensive Cancer Center [P30CA043703]
- CWRU Light Microscopy Imaging Center [S10OD016164]
- University of Chicago Genomics Facility
- NIH [R01NS034939]
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The study demonstrates that HIF1a impairs oligodendrocyte formation by activating non-canonical targets in OPCs, leading to the suppression of the oligodendrocyte regulator Sox10. Inhibition of MEK/ERK signaling can overcome this block in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. This research highlights the cell-type-specific HIF1a targets' role in perturbing cell function under low oxygen conditions.
Mammalian cells respond to insufficient oxygen through transcriptional regulators called hypoxia-inducible factors (HIFs). Although transiently protective, prolonged HIF activity drives distinct pathological responses in different tissues. Using a model of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyte progenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impair generation of oligodendrocytes from OPCs. HIF1a activated a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2. Non-canonical targets, including Ascl2 and Dlx3, were sufficient to block differentiation through suppression of the oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. MEK/ERK inhibition also drove oligodendrocyte formation in hypoxic regions of human oligocortical spheroids. This work defines mechanisms by which HIF1a impairs oligodendrocyte formation and establishes that cell-type-specific HIF1a targets perturb cell function in response to low oxygen.
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