BBB seminar: Giulio Cossu
Cell therapy of the Golden Retriever Muscular Dystrophy by systemic delivery of donor mesoangioblasts
Stem Cell Research Institute and Vita-Salute San Raffaele University, Milan, Italy
Muscular dystrophy primarily affects skeletal muscle causing fiber degeneration, progressive paralysis and, in the most severe forms, death. No efficacious therapy exist although new strategies are being developed with viral vectors, stem cells or molecules that counteract muscle degeneration. Mesoangioblasts are recently characterized stem cells that are associated with the vasculature and can differentiate in different types of solid mesoderm including skeletal muscle (Minasi et al. , Development 2002, 129:2773). When both wild type or dystrophic, genetically corrected, mesoangioblasts were delivered intra-arterially to dystrophic muscle of α-sarcoglycan null mice (a model for limb girdle muscular dystrophy), they resulted in a dramatic functional amelioration of the dystrophic phenotype (Sampaolesi et al. , Science 2003, 301:487). Here we report that intra-arterial or systemic delivery of wild type, non DLA matched mesoangioblasts results in a partial recovery of muscle morphology and function, dystrophin expression and clinical amelioration, which persisted for a few months after removal of immune suppression. Delivery of autologous mesoangioblasts expressing human micro-dystrophin did not cause a comparable amelioration, despite widespread micro-dystrophin expression. There results show efficacy of cell therapy in a large, immuno-competent animal and set the rationale for a future clinical trial.
Host: Donald Gullberg, Department of Biomedicine
Giulio Cossu is Professor of Histology and Embryology at the Vita-Salute San Raffaele University and Director of the Stem Cell Research Institute in Milan, Italy. He and his group have been working for a number of years on the signals and mechanism that regulate the formation of skeletal muscle during embryonic development and, after birth, when the muscle tissue is damaged as a result of an injury or a primary myopathy. Recently they have identified new, vessel-associated stem cells, called mesoangioblasts, and have shown that they ameliorate significantly muscular dystrophy in pre-clinical animal models.
Borello et al., 2006. The Wnt/beta-catenin pathway regulates Gli-mediated Myf5 expression during somitogenesis. Development 133:3723-32
Brunelli et al., 2004. Msx2 and necdin combined activities are required for smooth muscle differentiation in mesoangioblast stem cells. Circ. Res. 94:1571-78
Cossu, G., 2004. Fusion of bone marrow-derived stem cells with striated muscle may not be sufficient to activate muscle genes. J. Clin. Invest. 114:1540-43
Cossu, G. and Sampaolesi, M., 2004. New therapies for muscular dystrophy: cautious optimism. Trends Mol. Med. 10:516-20
Tagliafico et al., 2004. TGFbeta/BMP activate the smooth muscle/bone differentiation programs in mesoangioblasts. J. Cell Sci. 117:4377-88
Cossu, G. and Bianco, P., 2003. Mesoangioblasts--vascular progenitors for extravascular mesodermal tissues. Curr. Opin. Genet. Dev. 13:537-42