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

Autor:	Holley SM; Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Reidling JC; Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA., Cepeda C; Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Wu J; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Lim RG; Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA., Lau A; Psychiatry & Human Behavior, University of California Irvine, Irvine, CA 92697, USA., Moore C; Portland VA Medical Center, Portland, OR 97239, USA., Miramontes R; Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA., Fury B; Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA., Orellana I; Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA., Neel M; Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA., Coleal-Bergum D; Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA., Monuki ES; Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA., Bauer G; Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA., Meshul CK; Portland VA Medical Center, Portland, OR 97239, USA; Oregon Health & Science University, Department of Behavioral Neuroscience and Pathology, Portland, OR 97239, USA., Levine MS; Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Thompson LM; Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Psychiatry & Human Behavior, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA; Department of Neurobiology & Behavior University of California Irvine, Irvine, CA 92697, USA. Electronic address: lmthomps@uci.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 Dec 06; Vol. 31 (12), pp. 3545-3563. Date of Electronic Publication: 2023 Oct 07.
DOI:	10.1016/j.ymthe.2023.10.003
Abstrakt:	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. Competing Interests: Declaration of interests L.M.T. and J.C.R. have greater than 5% ownership in NeuroAirmid, a newly launched company that has related interests in cell therapy treatments for neurodegenerative diseases. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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