Human glial progenitors transplanted into Huntington disease mice normalize neuronal gene expression, dendritic structure, and behavior.

Neonatal glial replacement delays disease progression in mouse models of Huntington's disease (HD), in which glial dysfunction is prominent. Here, we ask if transplanting human glial progenitor cells (hGPCs) into adult R6/2 HD mice can ameliorate the phenotype, and how diseased host neurons are affected by healthy glia. We find that the introduction of hGPCs into the striata of adult R6/2 HD mice indeed slows their motor and cognitive decline and extends survival. Single-nucleus RNA sequencing (snRNA-seq) reveals that while genes associated with synaptic development and structure are downregulated in R6/2 striatal neurons, their transcription is partially rescued by healthy glia. Rabies labeling reveals that while dendritic complexity and spine density are deficient in R6/2 striatal neurons, each is largely restored by hGPC engraftment. These findings suggest that glial replacement in HD leads to partial normalization of neuronal gene expression, along with a restoration of dendritic complexity and delay in disease progression.