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 stromalderived 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 (>50%) followed by reconstitution of >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.