Format

Send to

Choose Destination
Cell Stem Cell. 2018 Aug 2;23(2):239-251.e6. doi: 10.1016/j.stem.2018.07.009.

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

Author information

1
Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
2
Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
3
Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
4
Integrative Genomics Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
5
The New York Stem Cell Foundation Research Institute, New York, NY 10019, USA.
6
New York Genome Center, New York, NY 10013, USA; Department of Biology, New York University, New York, NY 10003, USA; Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
7
Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: yshi@coh.org.

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.

KEYWORDS:

Alexander disease; CHI3L1; astrocytes; disease modeling; iPSCs; leukodystrophy; myelination; neurological disease; oligodendrocyte progenitor cells; oligodendrocytes

PMID:
30075130
PMCID:
PMC6230521
[Available on 2019-08-02]
DOI:
10.1016/j.stem.2018.07.009

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center