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

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. [Display omitted] •Mutant HTT-expressing hESCs exhibit a relative block in glial lineage progression•Differentiation-associated genes are downregulated in mHTT glial progenitor cells•Human glial chimeras established with mHTT glial progenitors are hypomyelinated•mHTT human glial chimeras manifest disrupted astrocytic differentiation The authors show that glial progenitor cells derived from human ESCs expressing mutant Huntingtin (mHTT) are delayed and defective in their maturation; their suppressed transcription of differentiation-associated genes leads to both astrocytic dysfunction and myelin deficiency in vivo. Glial pathology may thus contribute to disease phenotype in Huntington’s disease.