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

doi:10.1016/j.stemcr.2017.11.005

Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice

Stem Cell Reports. 2018 Jan 9;10(1):58-72. doi: 10.1016/j.stemcr.2017.11.005. Epub 2017 Dec 7.

Authors

Jack C Reidling¹, Aroa Relaño-Ginés², Sandra M Holley³, Joseph Ochaba⁴, Cindy Moore⁵, Brian Fury⁶, Alice Lau⁷, Andrew H Tran¹, Sylvia Yeung¹, Delaram Salamati¹, Chunni Zhu², Asa Hatami², Carlos Cepeda³, Joshua A Barry³, Talia Kamdjou³, Alvin King⁴, Dane Coleal-Bergum⁶, Nicholas R Franich², Frank M LaFerla⁸, Joan S Steffan⁹, Mathew Blurton-Jones¹⁰, Charles K Meshul¹¹, Gerhard Bauer⁶, Michael S Levine¹², Marie-Francoise Chesselet², Leslie M Thompson¹³

Affiliations

¹ Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA.
² Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA.
³ 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.
⁴ Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA.
⁵ Portland VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
⁶ Institute for Regenerative Cures, University of California, Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA.
⁷ Department of Psychiatry & Human Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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. Electronic address: lmthomps@uci.edu.

Abstract

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: Huntington's disease; Q140 mice; R6/2 mice; embryonic stem cells; neural stem cell; transplantation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line
Cognition*
Disease Models, Animal
Heterografts
Human Embryonic Stem Cells / metabolism
Human Embryonic Stem Cells / pathology
Humans
Huntington Disease / metabolism
Huntington Disease / pathology
Huntington Disease / physiopathology
Huntington Disease / therapy*
Mice
Motor Activity*
Neural Stem Cells / metabolism
Neural Stem Cells / pathology
Neural Stem Cells / transplantation*
Recovery of Function*

Abstract

Publication types

MeSH terms

Grants and funding