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Bisperoxovanadium, a phospho-tyrosine phosphatase inhibitor, reprograms myogenic cells to acquire a pluripotent, circulating phenotype

L. Castaldi^*,1, C. Serra^*,1,2, F. Moretti, G. Messina, R. Paoletti^*, M. Sampaolesi, A. Torgovnick, M. Baiocchi, F. Padula^*, A. Pisaniello^*, M. Molinaro^*, G. Cossu^,||, M. Levrero^,¶ and M. Bouché^*,3

^* Department of Histology and Medical Embryology, CE-BEMM and Interuniversity Institute of Myology, University of Rome "La Sapienza," Rome, Italy;

Fondazione A. Cesalpino, CRS Regina Elena Cancer Institute,

Stem Cell Research Institute, Dibit-H. San Raffaele, Milan, Italy;

Lab of Hematology, Istituto Superiore di Sanità, Rome, Italy;

^|| Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Italy; and

^¶ Department of Internal Medicine, University of Rome "La Sapienza," Rome, Italy

³Correspondence: Department of Histology and Med. Embr., Univ. of Rome "La Sapienza," Via A. Scarpa 14, 00161 Rome, Italy. E-mail: marina.bouche{at}uniroma1.it

Satellite cells are the main source of myogenic progenitors in postnatal skeletal muscle, but their use in cell therapy for muscle disorders is limited because these cells cannot be delivered through circulation and they are rapidly exhausted in severe myopathies. The search for alternative donor cells is ongoing, but none of the candidates so far show all the features required for successful colonization and repair of diseased muscle. In this study, we show that bisperoxovanadium, a phospho-tyrosine phosphatase inhibitor, induces myogenic cells to acquire a gene expression profile and a differentiation potential consistent with the phenotype of a circulating precursors, while maintaining their myogenic potential. These effects are mediated, at least in part, by NF-B activation through the Tyr42-IB- phosphorylation, as shown by the expression of the dominant negative mutant form of the p50 NF-B subunit. Moreover, when bisperoxovanadium-treated cells are injected into the femoral artery of -sarcoglican null dystrophic mice, they are able to circulate and to reach muscle tissue; importantly, they contribute to muscle regeneration, as shown by the expression of -sarcoglican in some fibers. Our observations indicate that bisperoxovanadium, or similar compounds, may prove very valuable to obtain and to expand, from committed cells, multipotent cell populations suitable for gene-cell therapy applications and may help to understand the molecular basis of genome reprogramming and "stem-ness."—Castaldi, L., Serra, C., Moretti, F., Messina, G., Paoletti, R., Sampaolesi, M., Torgovnick, A., Baiocchi, M., Padula, F., Pisaniello A., Molinaro, M., Cossu, G., Levrero, M., Bouché, M. Bisperoxovanadium, a phospho-tyrosine phosphatase inhibitor, reprograms myogenic cells to acquire a pluripotent, circulating phenotype.

Key Words: satellite cells • gene reprogramming • muscle deseases • cell therapy