期刊
CELL STEM CELL
卷 23, 期 2, 页码 239-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2018.07.009
关键词
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资金
- Herbert Horvitz Family
- Sidell Kagan Foundation
- California Institute for Regenerative Medicine [RB4-06277, TRAN1-08525]
- National Institute on Aging of the NIH [R01AG056305]
- Kimmel Foundation
- Melanoma Research Alliance
- National Human Genome Research Institute of the NIH [R00-HG008171, DP2-HG010099]
- National Cancer Institute of the NIH [P30CA33572]
Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by mutations in the astrocytic filament gene GFAP. While astrocytes are thought to have important roles in controlling myelination, AxD animal models do not recapitulate critical myelination phenotypes and it is therefore not clear how AxD astrocytes contribute to leukodystrophy. Here, we show that AxD patient iPSC-derived astrocytes recapitulate key features of AxD pathology such asGFAPaggregation. Moreover, AxD astrocytes inhibit proliferation of human iPSC-derived oligodendrocyte progenitor cells (OPCs) in co-culture and reduce their myelination potential. CRISPR/Cas9-based correction of GFAP mutations reversed these phenotypes. Transcriptomic analyses of AxD astrocytes and postmortem brains identified CHI3L1 as a key mediator of AxD astrocyte-induced inhibition of OPC activity. Thus, this iPSC-based model of AxD not only recapitulates patient phenotypes not observed in animal models, but also reveals mechanisms underlying disease pathology and provides a platform for assessing therapeutic interventions.
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