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GFAP Mutations in Astrocytes Impair Oligodendrocyte Progenitor Proliferation and Myelination in an hiPSC Model of Alexander Disease.

Abstract：

: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 as GFAP aggregation. 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.

journal_name

Cell Stem Cell

journal_title

Cell stem cell

authors

Li L,Tian E,Chen X,Chao J,Klein J,Qu Q,Sun G,Sun G,Huang Y,Warden CD,Ye P,Feng L,Li X,Cui Q,Sultan A,Douvaras P,Fossati V,Sanjana NE,Riggs AD,Shi Y

doi

10.1016/j.stem.2018.07.009

subject

Has Abstract

pub_date

2018-08-02 00:00:00

pages

239-251.e6

issue

2

eissn

1934-5909

issn

1875-9777

pii

S1934-5909(18)30345-X

journal_volume

23

pub_type

杂志文章

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