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Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington’s disease mice and innervate the striatum

Authors :
Holley, Sandra M.
Reidling, Jack C.
Cepeda, Carlos
Wu, Jie
Lim, Ryan G.
Lau, Alice
Moore, Cindy
Miramontes, Ricardo
Fury, Brian
Orellana, Iliana
Neel, Michael
Coleal-Bergum, Dane
Monuki, Edwin S.
Bauer, Gerhard
Meshul, Charles K.
Levine, Michael S.
Thompson, Leslie M.
Source :
Molecular Therapy; December 2023, Vol. 31 Issue: 12 p3545-3563, 19p
Publication Year :
2023

Abstract

Huntington’s disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

Details

Language :
English
ISSN :
15250016 and 15250024
Volume :
31
Issue :
12
Database :
Supplemental Index
Journal :
Molecular Therapy
Publication Type :
Periodical
Accession number :
ejs64169019
Full Text :
https://doi.org/10.1016/j.ymthe.2023.10.003