Human Mesenchymal Stem Cells Prolong Survival and Ameliorate Motor Deficit through Trophic Support in Huntington’s Disease Mouse Models Yuan-Ta Lin 1,2 , Yijuang Chern 3 , Che-Kun James Shen 2 , Hsin-Lan Wen 2 , Ya-Chin Chang 4 , Hung Li 1,2 , Tzu- Hao Cheng 1 , Hsiu Mei Hsieh-Li 4 * 1 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, 2 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, 3 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, 4 Department of Life Science, National Taiwan Normal University, Taipei, Taiwan 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. Citation: Lin Y-T, Chern Y, Shen C-KJ, Wen H-L, Chang Y-C, et al. (2011) Human Mesenchymal Stem Cells Prolong Survival and Ameliorate Motor Deficit through Trophic Support in Huntington’s Disease Mouse Models. PLoS ONE 6(8): e22924. doi:10.1371/journal.pone.0022924 Editor: Dimas Tadeu Covas, University of Sao Paulo – USP, Brazil Received February 16, 2011; Accepted July 2, 2011; Published August 5, 2011 Copyright: ß 2011 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Academia Sinica Grants AS-94-TP-B17, AS-97-TP-B02, and National Science Council Grant NSC 97-2320-B-003 -003 -MY3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: hmhsieh@ntnu.edu.tw Introduction 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. The disorder is characterized by intellectual decline, movement disorders and behavioral changes [1,2] that lead to severe debilitation and death, usually within 15–20 years. The neuropathological changes in HD are selective and progressive degeneration of striatal GABAergic medium spiny projection neurons [3] accounts for most of the clinical features. Currently, there is no proven medical therapy to alleviate the onset or progression of Huntington’s disease [4]. The clinical uses of cell replacement therapy in neurodegener- ative diseases have been investigated for the last 20 years. Although the procedures are theoretically feasible, some limita- tions of the therapy still give cause for concern. The transplan- tation of fetal striatal tissue to the striatum to modify HD progression in humans has been investigated, and some favorable effects have been found [5,6]. Transplanted fetal neurons can lead to functional benefit and repair [5], and the transplanted cells remain viable in the human neostriatum for long periods of time [6]. However, 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]. The use of renewable and expandable bone marrow-derived mesenchymal stem cells (BM-MSCs) circumvents many of the practical and ethical problems associated with the use of human fetal tissue. BM-MSCs are easy to acquire, have self-renewing properties, expand rapidly, and may differentiate into all of the major cell types in the central nervous system [8]. BM-MSCs can also be harvested directly from patients, with the resulting autologous transplants avoiding the risk of immune rejection [9]. Transplanted BM-MSCs have a reduced risk of tumor formation and are able to differentiate into neuronal or glial lineages and provide functional improvement in the central nervous systems (CNS) of rodents with Parkinson’s disease [10] and other neurodegenerative disorders [11,12]. We and others have demonstrated that intracerebrally transplanted bone marrow- derived stem cells can migrate to damaged brain areas and improve neuronal function and architecture in stroke animal models [8,13]. Furthermore, the function of neurogenic effects of human multipotent stromal cells (hMSCs) in HD mouse models had been demonstrated [14]. Therefore, MSCs may provide an PLoS ONE | www.plosone.org 1 August 2011 | Volume 6 | Issue 8 | e22924