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First published online December 11, 2006
doi: 10.1242/10.1242/jcs.03300

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Ex vivo treatment with nitric oxide increases mesoangioblast therapeutic efficacy in muscular dystrophy

Clara Sciorati^1,*, Beatriz G. Galvez^1,*, Silvia Brunelli^1,2,*, Enrico Tagliafico³, Stefano Ferrari³, Giulio Cossu^1,4, and Emilio Clementi^1,5,6,

¹ CellStem Cell Research Institute, H. San Raffaele Scientific Institute, 20132, Milan, Italy
² Department of Experimental, Environmental Medicine and Medical Biotechnology, University of Milano-Bicocca, 20052 Monza, Italy
³ Department of Biomedical Science, University of Modena and Reggio Emilia, 41100 Modena, Italy
⁴ Department of Biology, University of Milano, 20130 Milan, Italy
⁵ E. Medea Scientific Institute, 23842 Bosisio Parini, Italy
⁶ Department of Preclinical Sciences LITA-Vialba, University of Milano, 20157 Milan, Italy

Authors for correspondence (e-mail: giulio.cossu{at}unimi.it and emilio.clementi{at}unimi.it)

Accepted 12 October 2006

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 -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 -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.

Key words: Muscular dystrophy, Stem cells, Nitric oxide, Cyclic GMP, Apoptosis, Differentiation

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NO limit to muscular dystrophy

JCS 2006 119: 2404. [Full Text]  

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