Stem Cell Reports (Jan 2018)
Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice
- Jack C. Reidling,
- Aroa Relaño-Ginés,
- Sandra M. Holley,
- Joseph Ochaba,
- Cindy Moore,
- Brian Fury,
- Alice Lau,
- Andrew H. Tran,
- Sylvia Yeung,
- Delaram Salamati,
- Chunni Zhu,
- Asa Hatami,
- Carlos Cepeda,
- Joshua A. Barry,
- Talia Kamdjou,
- Alvin King,
- Dane Coleal-Bergum,
- Nicholas R. Franich,
- Frank M. LaFerla,
- Joan S. Steffan,
- Mathew Blurton-Jones,
- Charles K. Meshul,
- Gerhard Bauer,
- Michael S. Levine,
- Marie-Francoise Chesselet,
- Leslie M. Thompson
Affiliations
- Jack C. Reidling
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Aroa Relaño-Ginés
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
- Sandra M. Holley
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
- Joseph Ochaba
- Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Cindy Moore
- Portland VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA
- Brian Fury
- Institute for Regenerative Cures, University of California, Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA
- Alice Lau
- Department of Psychiatry & Human Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Andrew H. Tran
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Sylvia Yeung
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Delaram Salamati
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Chunni Zhu
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
- Asa Hatami
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
- Carlos Cepeda
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
- Joshua A. Barry
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
- Talia Kamdjou
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
- Alvin King
- Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Dane Coleal-Bergum
- Institute for Regenerative Cures, University of California, Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA
- Nicholas R. Franich
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
- Frank M. LaFerla
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Joan S. Steffan
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Psychiatry & Human Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
- Mathew Blurton-Jones
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Sue and Bill Gross Stem Cell Center, University of California, Irvine, Gross Hall, Room 3219, 845 Health Sciences Road, Irvine, CA 92697, USA
- Charles K. Meshul
- Portland VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA; Oregon Health & Science University, Department of Behavioral Neuroscience, 3181 SW Sam Jackson Park Road, L470, Portland, OR 97239, USA
- Gerhard Bauer
- Institute for Regenerative Cures, University of California, Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA
- Michael S. Levine
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
- Marie-Francoise Chesselet
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
- Leslie M. Thompson
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Psychiatry & Human Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Sue and Bill Gross Stem Cell Center, University of California, Irvine, Gross Hall, Room 3219, 845 Health Sciences Road, Irvine, CA 92697, USA; Corresponding author
- DOI
- https://doi.org/10.1016/j.stemcr.2017.11.005
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 58 – 72
Abstract
Summary: Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies.
Keywords
