hESC-based human glial chimeric mice reveal glial differentiation defects in Huntington disease

Huntington’s disease (HD) is characterized by hypomyelination as well as 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 huntingtin (mHTT)-mutant embryos or normal controls, and performed RNAseq to assess mHTT-dependent changes in gene expression. In hGPCs derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply down-regulated 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.亨廷顿舞蹈症（Huntington’s disease, HD）以髓鞘形成不足及神经元丢失为特征。为探究HD中髓鞘丢失的潜在机制，本研究从携带亨廷顿蛋白（mHTT）突变的人类胚胎干细胞（human embryonic stem cells, hESCs）及正常对照胚胎中，分别诱导得到双潜能胶质祖细胞（bipotential glial progenitor cells, GPCs），并通过RNA测序（RNA-seq）分析mHTT依赖性的基因表达变化。在来自3株mHTT突变hESC系的hGPCs中，与胶质细胞分化及髓鞘合成相关的转录因子相较于正常hESC来源的GPCs显著下调；NKX2.2、OLIG2、SOX10、MYRF及其下游靶基因均受到抑制。相应地，当将mHTT突变hGPCs移植至髓鞘形成不足的震颤小鼠（shiverer mice）体内时，所形成的胶质嵌合体呈现髓鞘形成不足表型；该缺陷可通过在mHTT突变hGPCs中强制过表达SOX10与MYRF得以挽救。mHTT突变hGPCs同时表现出星形胶质细胞分化受损，并出现异常纤维结构。综上，HD中的白质萎缩是细胞自主性的、mHTT依赖性的胶质细胞分化抑制的结果。