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

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Publication Year:
2018
Authors:
Li Li, E Tian, Xianwei Chen, Jianfei Chao, Jeremy Klein, Qiuhao Qu, Guihua Sun, Guoqiang Sun, Yanzhou Huang, Charles D Warden, Peng Ye, Lizhao Feng, Xinqiang Li, Qi Cui, Abdullah Sultan, Panagiotis Douvaras, Valentina Fossati, Neville E Sanjana, Arthur D Riggs, Yanhong Shi
PubMed ID:
30075130
Funding Grants:
Public Summary:
Alexander disease (AxD) is a brain disease that primarily affects star-shaped cells in the brain and is caused by mutations in a gene called GFAP. While the star-shaped cells in the brain 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 the star-shaped cells in the brains of AxD patients contribute to myelination defect. Here, we show that the star-shaped cells generated from AxD patient-derived induced pluripotent stem cells (iPSCs) recapitulate key features of AxD pathology such as aggregation of the GFAP protein. Moreover, the star-shaped cells generated from AxD patient iPSCs inhibit proliferation of oligodendrocyte progenitor cells (OPCs) in co-culture and reduce their myelination potential. CRISPR/Cas9-based correction of GFAP mutations reversed these phenotypes. Gene profiling analyses of the star-shaped cells generated from AxD patient iPSCs and postmortem patient brains identified CHI3L1 as a key mediator of OPC activity inhibition by the star-shaped cells generated from AxD patient iPSCs. 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.
Scientific 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.