Journal
STEM CELL REPORTS
Volume 11, Issue 3, Pages 711-726Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2018.07.015
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Funding
- European Leukodystrophy Association
- NIH [R01NS093357, R01HG009658, T32GM007250]
- New York Stem Cell Foundation
- Cytometry & Microscopy, Genomics, Imaging, and Small Molecule Drug Development core facilities of the Case Western Reserve University (CWRU) Comprehensive Cancer Center [P30CA043703]
- High Performance Computing Resource in the Core Facility for Advanced Research Computing at CWRU
- Cleveland Clinic Lerner Research Institute Imaging Core
- CWRU Light Microscopy Core Facility (NIH grant) [S10-OD016164]
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Pelizaeus-Merzbacher disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of induced pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp(1jimpy). Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25-6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy, in vitro and in vivo, and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination.
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