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

Sandra M Holley; Jack C Reidling; Carlos Cepeda; Jie Wu; Ryan G Lim; Alice Lau; Cindy Moore; Ricardo Miramontes; Brian Fury; Iliana Orellana; Michael Neel; Dane Coleal-Bergum; Edwin S Monuki; Gerhard Bauer; Charles K Meshul; Michael S Levine; Leslie M Thompson

doi:10.1016/j.ymthe.2023.10.003

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

Mol Ther. 2023 Dec 6;31(12):3545-3563. doi: 10.1016/j.ymthe.2023.10.003. Epub 2023 Oct 7.

Authors

Sandra M Holley¹, Jack C Reidling², Carlos Cepeda¹, Jie Wu³, Ryan G Lim², Alice Lau⁴, Cindy Moore⁵, Ricardo Miramontes², Brian Fury⁶, Iliana Orellana², Michael Neel⁷, Dane Coleal-Bergum⁶, Edwin S Monuki⁸, Gerhard Bauer⁶, Charles K Meshul⁹, Michael S Levine¹⁰, Leslie M Thompson¹¹

Affiliations

¹ 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.
² Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
³ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁴ Psychiatry & Human Behavior, University of California Irvine, Irvine, CA 92697, USA.
⁵ Portland VA Medical Center, Portland, OR 97239, USA.
⁶ Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA.
⁷ Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92697, USA.
⁸ 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.
⁹ Portland VA Medical Center, Portland, OR 97239, USA; Oregon Health & Science University, Department of Behavioral Neuroscience and Pathology, Portland, OR 97239, USA.
¹⁰ 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.
¹¹ 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.

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.

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

MeSH terms

Animals
Corpus Striatum
Disease Models, Animal
Humans
Huntingtin Protein / genetics
Huntington Disease* / genetics
Huntington Disease* / therapy
Mice
Mice, Transgenic
Neural Stem Cells*
Neurons
Phenotype

Substances

Huntingtin Protein

Abstract

MeSH terms

Substances

Grants and funding