title: Ex vivo treatment with nitric oxide increases mesoangioblast therapeutic efficacy in muscular dystrophy.
abstract: Muscular dystrophies are characterized by primary wasting of skeletal muscle for which no satisfactory therapy is available. Studies in animal models have shown that stem cell-based therapies may improve the outcome of the disease, and that mesoangioblasts are promising stem cells in this respect. The efficacy of mesoangioblasts in yielding extensive muscle repair is, however, still limited. We found that mesoangioblasts treated with nitric oxide (NO) donors and injected intra-arterially in alpha-sarcoglycan-null dystrophic mice have a significantly enhanced ability to migrate to dystrophic muscles, to resist their apoptogenic environment and engraft into them, yielding a significant recovery of alpha-sarcolgycan expression. In vitro NO-treated mesoangioblasts displayed an enhanced chemotactic response to myotubes, cytokines and growth factors generated by the dystrophic muscle. In addition, they displayed an increased ability to fuse with myotubes and differentiating myoblasts and to survive when exposed to cytotoxic stimuli similar to those present in the dystrophic muscle. All the effects of NO were cyclic GMP-dependent since they were mimicked by treatment with the membrane permeant cyclic-GMP analogue 8-bromo-cGMP and prevented by inhibiting guanylate cyclase. We conclude that NO donors exert multiple beneficial effects on mesoangioblasts that may be used to increase their efficacy in cell therapy of muscular dystrophies.
authors.affiliation: Stem Cell Research Institute, H San Raffaele Scientific Institute, 20132, Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Sciorati
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Galvez
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliafico
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000628:therapy*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D020030:Nitric Oxide Donors; D049031:Sarcoglycans; D006152:Cyclic GMP