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Cell Stem Cell. 2019 Jan 3;24(1):107-122.e7. doi: 10.1016/j.stem.2018.11.010. Epub 2018 Dec 13.

Human ESC-Derived Chimeric Mouse Models of Huntington's Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation.

Author information

1
Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Science, 2200 Copenhagen N, Denmark.
2
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 10021, USA.
3
Center for Translational Neuromedicine, University of Copenhagen Faculty of Health and Medical Science, 2200 Copenhagen N, Denmark; Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 10021, USA; Neuroscience Center, Rigshospitalet, Copenhagen, Denmark. Electronic address: steven_goldman@urmc.rochester.edu.

Abstract

Huntington's disease (HD) is characterized by hypomyelination and neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs) derived from mutant Huntingtin (mHTT) embryos or normal controls and performed RNA sequencing (RNA-seq) to assess mHTT-dependent changes in gene expression. In human GPCs (hGPCs) derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply downregulated relative to normal hESC GPCs; NKX2.2, OLIG2, SOX10, MYRF, and their downstream targets were all suppressed. Accordingly, when mHTT hGPCs were transplanted into hypomyelinated shiverer mice, the resultant glial chimeras were hypomyelinated; this defect could be rescued by forced expression of SOX10 and MYRF by mHTT hGPCs. The mHTT hGPCs also manifested impaired astrocytic differentiation and developed abnormal fiber architecture. White matter involution in HD is thus a product of the cell-autonomous, mHTT-dependent suppression of glial differentiation.

KEYWORDS:

Huntington’s disease; MYRF; astrocyte; chimera; chimeric mouse; embryonic stem cell; glia; myelin; neurodegenerative disease; oligodendrocyte

PMID:
30554964
DOI:
10.1016/j.stem.2018.11.010

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