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.

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*