Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

Abdellatif Benraiss,Devin Chandler-Militello,Mikhail Osipovitch,Daniela Brunner,Xiaojie Li,Ning Kang,Martha S Windrem,Fushun Wang,Su Wang,Steven A Goldman,Hayley B Burm,Jian Kang,Stephanie Herrlinger,Joseph Mauceri,Paul Curtin ,Ignacio Muñoz-Sanjuán ,Qiwu Xu ,Michael J Toner ,Feng Ding

doi:10.1038/ncomms11758

Abstract

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder.

Highlights

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored
We identified a specific role for human striatal glia in the pathogenesis of HD, by comparing the behaviour and medium spiny neurons (MSNs) physiology of human glial chimeric mice xenografted at birth with mutant HD-expressing human human glial progenitor cells (hGPCs) to their normal HTT hGPC-engrafted controls
A number of recent reports have highlighted the contribution of glial cells to the pathogenesis of neurodegenerative disorders, most in the spinal cord, in which glial pathology has been implicated in the course of amyotrophic lateral sclerosis[1,2,4,5]

Summary

Introduction

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. We identified a specific role for human striatal glia in the pathogenesis of HD, by comparing the behaviour and MSN physiology of human glial chimeric mice xenografted at birth with mutant HD-expressing human hGPCs to their normal HTT hGPC-engrafted controls. We found that the substantial replacement of diseased striatal glia with wild-type (WT) CD44 þ human glia resulted in a slowing of disease progression, and a corresponding increment in survival in transplanted R6/2 mice This was associated with a transplant-associated fall in neuronal input resistance, and a corresponding drop in interstitial K þ in the R6/2 striatum. These studies suggest both a critical role for glial pathology in the progression of HD, and the potential for glial cell replacement as a strategy for its treatment

Methods

Results

Conclusion