Human ESC-derived chimeric mouse models of Huntington's disease reveal cell-intrinsic defects in glial progenitor cell differentiation
Open accessAbstract
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.
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hiPSC glial mouse chimeric brains offer the possibility to study human astrocytes from patients in contexts amenable to in vivo experimentation.
“hiPSC glial mouse chimeric brains, in which hiPSC differentiate into human astrocytes, oligodendrocytes, and their progenitors, offer the possibility to study human astrocytes from patients in contexts amenable to in vivo experimentation113,114”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [114]
The Results section ('mHTT impairs human astroglial differentiation in vivo'; page not provided) describes studying human astrocytes in glial-engrafted mouse brains, supporting the in vivo model. But the Experimental Model section (page not provided) says the Huntington’s disease glial progenitors came from human embryonic stem cells, not patient-derived hiPSCs; the iPSC line mentioned in the Results was a control. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIntrastriatal engraftment of mHTT-expressing human glial progenitor cells in immunodeficient mice results in neuronal hyperexcitability in the striatum along with motor impairments.
“Furthermore, intrastriatal engraftment of mHTT-expressing human glial progenitor cells in immunodeficient mice results in neuronal hyperexcitability in the striatum along with motor impairments (Benraiss et al. , 2016; Osipovitch et al. , 2019).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Osipovitch et al., 2019
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- Authors
- Osipovitch, M., Asenjo Martinez, A., Mariani, J. N., Cornwell, A., Dhaliwal, S., Zou, L., Chandler-Militello, D., Wang, S., Li, X., Benraiss, S.-J., Agate, R., Lampp, A., Benraiss, A., Windrem, M. S., & Goldman, S. A.
- Affiliations
- University of Copenhagen (DK)
- University of Rochester Medicine (US)
- Corresponding author
- Goldman, Steven A.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 24
- Issue
- 1
- Pages
- 107-122.e7
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6700734
- OpenAlex
- W2904655759
- Cited by
- 120
- References
- 46
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 13 · 2023: 24 · 2022: 26 · 2021: 12 · 2020: 9 · 2019: 9
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Novo Nordisk Fonden
- CHDI Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- Lundbeckfonden
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- Huntington's disease, human embryonic stem cells, glial progenitor cells, mutant huntingtin, hypomyelination, demyelination, glial differentiation, SOX10, MYRF, Nkx2.2, Olig2, shiverer mice, astrocyte differentiation
- MeSH terms
- Human Embryonic Stem Cells, Huntingtin Protein, Homeobox Protein Nkx-2.2, Animals, Astrocytes, Cell Differentiation, Chimera, Demyelinating Diseases, Disease Models, Animal, Humans, Huntington Disease, Mutation, Neuroglia, Nuclear Proteins, Stem Cells, Transcription Factors, Homeodomain Proteins, Mice, Neurogenesis
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