Abstract
We investigated the therapeutic potential of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in Huntington's disease (HD) mouse models. Ten weeks after intrastriatal injection of quinolinic acid (QA), mice that received hBM-MSC transplantation showed a significant reduction in motor function impairment and increased survival rate. Transplanted hBM-MSCs were capable of survival, and inducing neural proliferation and differentiation in the QA-lesioned striatum. In addition, the transplanted hBM-MSCs induced microglia, neuroblasts and bone marrow-derived cells to migrate into the QA-lesioned region. Similar results were obtained in R6/2-J2, a genetically-modified animal model of HD, except for the improvement of motor function. After hBM-MSC transplantation, the transplanted hBM-MSCs may integrate with the host cells and increase the levels of laminin, Von Willebrand Factor (VWF), stromal cell-derived factor-1 (SDF-1), and the SDF-1 receptor Cxcr4. The p-Erk1/2 expression was increased while Bax and caspase-3 levels were decreased after hBM-MSC transplantation suggesting that the reduced level of apoptosis after hBM-MSC transplantation was of benefit to the QA-lesioned mice. Our data suggest that hBM-MSCs have neural differentiation improvement potential, neurotrophic support capability and an anti-apoptotic effect, and may be a feasible candidate for HD therapy.
Highlights
Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no effective treatment
We demonstrated that hBM-Mesenchymal stem cells (MSCs) transplantation may have beneficial effects by increasing neurogenesis, attracting neural stem-cell migration, enhancing stromal cell-derived factor-1 (SDF-1) expression, and decreasing apoptosis in mouse models of HD
Our results showed that GFAP, NeuN, and DARPP-32 were all not detected in the hBM-MSCs before transplantation into mouse striata
Summary
Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no effective treatment. It is caused by an unstable expansion mutation of a naturally occurring trinucleotide (CAG) repeat in exon 1 of the IT15 gene on chromosome 4p16.3 that encodes a ubiquitously expressed 350-kDa protein named huntingtin. There are still many unsolved difficulties associated with the transplantation of human fetal striatal tissue for therapy in HD such as ethical arguments, viability of tissue source, limitations on tissue acceptance, the high risk of rejection and concerns about contamination and heterogeneity of the tissues [7]
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