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

Abdellatif Benraiss; Su Wang; Stephanie Herrlinger; Xiaojie Li; Devin Chandler-Militello; Joseph Mauceri; Hayley B. Burm; Michael Toner; Mikhail Osipovitch; Qiwu Jim Xu; Fengfei Ding; Fushun Wang; Ning Kang; Jian Kang; Paul C. Curtin; Daniela Brunner; Martha S. Windrem; Ignacio Munoz-Sanjuan; Maiken Nedergaard; Steven A. Goldman

doi:10.1038/ncomms11758

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

Abdellatif Benraiss, Su Wang, Stephanie Herrlinger, Xiaojie Li, Devin Chandler-Militello, Joseph Mauceri, Hayley B. Burm, Michael Toner, Mikhail Osipovitch, Qiwu Jim Xu, Fengfei Ding, Fushun Wang, Ning Kang, Jian Kang, Paul C. Curtin, Daniela Brunner, Martha S. Windrem, Ignacio Munoz-Sanjuan, Maiken Nedergaard, Steven A. Goldman

76 Citations (Scopus)

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.

Original language	English
Article number	11758
Journal	Nature Communications
Volume	7
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms11758
Publication status	Published - 7 Jun 2016

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Benraiss, A., Wang, S., Herrlinger, S., Li, X., Chandler-Militello, D., Mauceri, J., Burm, H. B., Toner, M., Osipovitch, M., Jim Xu, Q., Ding, F., Wang, F., Kang, N., Kang, J., Curtin, P. C., Brunner, D., Windrem, M. S., Munoz-Sanjuan, I., Nedergaard, M., & Goldman, S. A. (2016). Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nature Communications, 7, Article 11758. https://doi.org/10.1038/ncomms11758

Benraiss, A, Wang, S, Herrlinger, S, Li, X, Chandler-Militello, D, Mauceri, J, Burm, HB, Toner, M, Osipovitch, M, Jim Xu, Q, Ding, F, Wang, F, Kang, N, Kang, J, Curtin, PC, Brunner, D, Windrem, MS, Munoz-Sanjuan, I, Nedergaard, M & Goldman, SA 2016, 'Human glia can both induce and rescue aspects of disease phenotype in Huntington disease', Nature Communications, vol. 7, 11758. https://doi.org/10.1038/ncomms11758

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title = "Human glia can both induce and rescue aspects of disease phenotype in Huntington disease",

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.",

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AU - Benraiss, Abdellatif

AU - Wang, Su

AU - Herrlinger, Stephanie

AU - Li, Xiaojie

AU - Chandler-Militello, Devin

AU - Mauceri, Joseph

AU - Burm, Hayley B.

AU - Toner, Michael

AU - Osipovitch, Mikhail

AU - Jim Xu, Qiwu

AU - Ding, Fengfei

AU - Wang, Fushun

AU - Kang, Ning

AU - Kang, Jian

AU - Curtin, Paul C.

AU - Brunner, Daniela

AU - Windrem, Martha S.

AU - Munoz-Sanjuan, Ignacio

AU - Nedergaard, Maiken

AU - Goldman, Steven A.

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N2 - 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.

AB - 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.

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DO - 10.1038/ncomms11758

M3 - Journal article

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SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11758

ER -

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

Abstract

Keywords

UN SDGs

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