Increased myogenic potential and fusion of matrilysin-expressing myoblaststransplanted in mice

The success of myoblast transplantation in clinical trials has been limited in part by the low dispersion of grafted cells outside the injection site. Our research group previously reported that the culture of myoblasts with concanavalin A, a stimulator of metalloproteinase production, increased the ir migration. Several lines of evidence also suggested that muscle cell fus ion involves metalloproteinase-sensitive mechanisms. To determine whether t he increased expression of metalloproteinases had an influence on myoblast fission and dispersion through the muscle following transplantation, we gen erated a myoblast cell line expressing human matrilysin (MMP-7). The MMP-7- expressing myoblasts were obtained by the stable transfection of a matrilys in expression vector in a TnILacZ immortomouse myoblast clone. Matrilysin-e xpressing myoblasts showed a highly increased in vitro fusion index, formin g seven times (p < 0.001) more myotubes than the control cell line and thre e times (p,< 0.001) more myotubes than the Immortomyoblast parental clone. Single-site transplantation of matrilysin-expressing myoblasts generated mo re fibers (p < 0.001), over a greater surface (p < 0.001) than the control cell line. The cotransplantation of matrilysin-expressing myoblasts and of normal human myoblasts in SCID mice increased the number of human dystrophi n-positive fibers and myotubes by sixfold. Although no significant increase d migration of myoblasts outside the injection sites was observed, our resu lts show that the metalloproteinase activity can improve the myogenic poten tial of myoblasts in vitro and the fusion of myoblasts with host fibers in vivo. MMP-7 expression may be useful in increasing myoblast transplantation success.