Implantation of undifferentiated and pre-differentiated human neural stem cells in the R6/2 transgenic mouse model of Huntington's disease

BMC Neurosci. 2012 Aug 9;13:97. doi: 10.1186/1471-2202-13-97.

Abstract

Background: Cell therapy is a potential therapeutic approach for several neurodegenetative disease, including Huntington Disease (HD). To evaluate the putative efficacy of cell therapy in HD, most studies have used excitotoxic animal models with only a few studies having been conducted in genetic animal models. Genetically modified animals should provide a more accurate representation of human HD, as they emulate the genetic basis of its etiology.

Results: In this study, we aimed to assess the therapeutic potential of a human striatal neural stem cell line (STROC05) implanted in the R6/2 transgenic mouse model of HD. As DARPP-32 GABAergic output neurons are predominately lost in HD, STROC05 cells were also pre-differentiated using purmorphamine, a hedgehog agonist, to yield a greater number of DARPP-32 cells. A bilateral injection of 4.5x105 cells of either undifferentiated or pre-differentiated DARPP-32 cells, however, did not affect outcome compared to a vehicle control injection. Both survival and neuronal differentiation remained poor with a mean of only 161 and 81 cells surviving in the undifferentiated and differentiated conditions respectively. Only a few cells expressed the neuronal marker Fox3.

Conclusions: Although the rapid brain atrophy and short life-span of the R6/2 model constitute adverse conditions to detect potentially delayed treatment effects, significant technical hurdles, such as poor cell survival and differentiation, were also sub-optimal. Further consideration of these aspects is therefore needed in more enduring transgenic HD models to provide a definite assessment of this cell line's therapeutic relevance. However, a combination of treatments is likely needed to affect outcome in transgenic models of HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavioral Symptoms / etiology
  • Behavioral Symptoms / surgery
  • Body Weight / genetics
  • Cell Differentiation / genetics
  • Cell Survival / genetics
  • Corpus Striatum / cytology
  • Corpus Striatum / embryology
  • Disease Models, Animal
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • Exploratory Behavior / physiology
  • Female
  • Fetus
  • Hand Strength / physiology
  • Hepatocyte Nuclear Factor 3-gamma / metabolism
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology
  • Huntington Disease / surgery*
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / genetics
  • Nerve Tissue Proteins / genetics
  • Neural Stem Cells / physiology
  • Neural Stem Cells / transplantation*
  • Rotarod Performance Test
  • Transfection
  • Trinucleotide Repeats / genetics

Substances

  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Foxa3 protein, mouse
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Hepatocyte Nuclear Factor 3-gamma