Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability

Efficient delivery of cells to target tissues is a major problem in cell therapy. We report that enhancing delivery of mesoangioblasts leads to a complete reconstitution of downstream skeletal muscles in a mouse model of severe muscular dystrophy ((alpha)-sarcoglycan ko). Mesoangioblasts, vessel-associated stem cells, were exposed to several cytokines, among which stromal-derived factor (SDF) 1 or tumor necrosis factor (TNF) (alpha) were the most potent in enhancing transmigration in vitro and migration into dystrophic muscle in vivo. Transient expression of (alpha)4 integrins or L-selectin also increased several fold migration both in vitro and in vivo. Therefore, combined pretreatment with SDF-1 or TNF-(alpha) and expression of (alpha)4 integrin leads to massive colonization (&rt;50%) followed by reconstitution of &rt;80% of (alpha)-sarcoglycan-expressing fibers, with a fivefold increase in efficiency in comparison with control cells. This study defines the requirements for efficient engraftment of mesoangioblasts and offers a new potent tool to optimize future cell therapy protocols for muscular dystrophies. (copyright) The Rockefeller University Press.