Tackling Huntington’s disease with stem cell therapy in mice

The neurodegenerative disorder Huntingtons disease (HD) is characterised by diminished muscle coordination, cognitive impairment and behavioural changes. It is a genetic disorder caused by the expansion of a CAG trinucleotide repeat in the gene encoding the huntingtin protein. This results in the degeneration of nerve cells, starting with those in the striatum of the brain. At present there is no treatment for this disease, nor any means to slow down its progression. Current therapies therefore focus on managing symptoms. Research is underway to determine whether stem cell therapies could reduce the neuropathological deficits brought on by HD and in doing so slow disease progression. A recent study published in Stem Cell Research & Therapy by Gary Dunbar from Central Michigan University, USA and colleagues, probes the potential of mesenchymal stem cells in treating a mouse model of HD.

Immunohistochemical analysis of low passage (left) and high passage (right) umbilical cord mesenchymal stem cells (blue) transplanted into the striata of R6/2 mice. Stained for NeuN (red) and GFAP (green). Image source: Fink et al, Stem Cell Research & Therapy, 2013, 4:130

Dunbar and colleagues used the R6/2 mouse model of HD to test the efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs). R6/2 mice express the N-terminal portion of the human huntingtin gene, containing a highly expanded CAG repeat, and consequently develop progressive neurological phenotypes resembling the disease in humans. At five weeks of age, R6/2 mice were transplanted with either low passage or high passage UC-MSCs, and were followed for six weeks. The mice underwent a number of behavioural tests, including the rotarod task to assess balance, the Morris water maze and the limb-clasping response. They were subsequently sacrificed for histological analysis. Wild-type and sham-operated R6/2 mice served as the controls.

R6/2 mice treated with high passage UC-MSCs performed better on the rotarod task compared with untreated R6/2 mice at ten weeks of age, although the improvement was transient. The most promising effects of treatment with high passage UC-MSCs were seen in the reduction of neuropathological deficits. The researchers found that untreated R6/2 mice had significantly smaller brain areas than wild-type animals, suggesting brain atrophy. This effect was mitigated in mice treated with high passage UC-MSCs, which showed no difference from wild-type mice in measures of brain area. Transplantation of high passage UC-MSCs into R6/2 mice also preserved substantially more metabolic activity in striatal brain tissue compared with untreated animals.

Although no long-term effects on behaviour were observed in this study, the fact that UC-MSCs significantly reduced neuropathological deficits suggests that stem cells could have therapeutic value in the management of HD.

Transplantation of umbilical cord-derived mesenchymal stem cells into the striata of R6/2 mice: behavioral and neuropathological analysis

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Tackling Huntington’s disease with stem cell therapy in mice

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