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

BDNF Huntington’s disease electron microscopy electrophysiology neural stem cells single-nucleus RNA-seq stem cells zQ175 mice

Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
06 Dec 2023
Historique:
received: 25 04 2023
revised: 28 08 2023
accepted: 04 10 2023
pubmed: 9 10 2023
medline: 9 10 2023
entrez: 9 10 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ymthe.2023.10.003 PMID: 37807512
pubmed: 37807512
pii: S1525-0016(23)00544-0
doi: 10.1016/j.ymthe.2023.10.003
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

3545-3563

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Sandra M 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.

Jack C Reidling (JC)

Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.

Carlos 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.

Jie Wu (J)

Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.

Ryan G Lim (RG)

Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.

Alice Lau (A)

Psychiatry & Human Behavior, University of California Irvine, Irvine, CA 92697, USA.

Cindy Moore (C)

Portland VA Medical Center, Portland, OR 97239, USA.

Ricardo Miramontes (R)

Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.

Brian Fury (B)

Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA.

Iliana Orellana (I)

Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.

Michael Neel (M)

Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA.

Dane Coleal-Bergum (D)

Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA.

Edwin S 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.

Gerhard Bauer (G)

Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA.

Charles K Meshul (CK)

Portland VA Medical Center, Portland, OR 97239, USA; Oregon Health & Science University, Department of Behavioral Neuroscience and Pathology, Portland, OR 97239, USA.

Michael S 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.

Leslie M 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.

Classifications MeSH