Bisperoxovanadium, a phospho-tyrosine phosphatase inhibitor, reprograms myogenic cells to acquire a pluripotent, circulating phenotype.
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-kappaB activation through the Tyr42-IkappaB-alpha phosphorylation, as shown by the expression of the dominant negative mutant form of the p50 NF-kappaB subunit. Moreover, when bisperoxovanadium-treated cells are injected into the femoral artery of alpha-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 alpha-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
L
Department of Histology and Med. Embr., Univ. of Rome La Sapienza, Via A. Scarpa 14, 00161 Rome, Italy.
Serra
C
C
Moretti
F
F
Messina
G
G
Paoletti
R
R
Sampaolesi
M
M
Torgovnick
A
A
Baiocchi
M
M
Padula
F
F
Pisaniello
A
A
Molinaro
M
M
Cossu
G
G
Levrero
M
M
Bouché
M
M
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D002460:Cell Line; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006321:Heart / Q000187:drug effects*; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017968:Vanadium Compounds / Q000494:pharmacology*
D017931:DNA Primers; D004791:Enzyme Inhibitors; D017968:Vanadium Compounds; C472777:bisperoxovanadium; D017027:Protein Tyrosine Phosphatases