Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
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| Enthalten in: |
Molecular therapy : the journal of the American Society of Gene Therapy - 31(2023), 12 vom: 06. Dez., Seite 3545-3563 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Holley, Sandra M [VerfasserIn] |
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| Links: |
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| Themen: |
BDNF |
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| Anmerkungen: |
Date Completed 16.12.2023 Date Revised 31.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ymthe.2023.10.003 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Holley, Sandra M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum |
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| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BDNF | |
| 650 | 4 | |a Huntington’s disease | |
| 650 | 4 | |a electron microscopy | |
| 650 | 4 | |a electrophysiology | |
| 650 | 4 | |a neural stem cells | |
| 650 | 4 | |a single-nucleus RNA-seq | |
| 650 | 4 | |a stem cells | |
| 650 | 4 | |a zQ175 mice | |
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| 700 | 1 | |a Reidling, Jack C |e verfasserin |4 aut | |
| 700 | 1 | |a Cepeda, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Ryan G |e verfasserin |4 aut | |
| 700 | 1 | |a Lau, Alice |e verfasserin |4 aut | |
| 700 | 1 | |a Moore, Cindy |e verfasserin |4 aut | |
| 700 | 1 | |a Miramontes, Ricardo |e verfasserin |4 aut | |
| 700 | 1 | |a Fury, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Orellana, Iliana |e verfasserin |4 aut | |
| 700 | 1 | |a Neel, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Coleal-Bergum, Dane |e verfasserin |4 aut | |
| 700 | 1 | |a Monuki, Edwin S |e verfasserin |4 aut | |
| 700 | 1 | |a Bauer, Gerhard |e verfasserin |4 aut | |
| 700 | 1 | |a Meshul, Charles K |e verfasserin |4 aut | |
| 700 | 1 | |a Levine, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a Thompson, Leslie M |e verfasserin |4 aut | |
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