Transplantation of Myoblast Sheets that Secrete the Novel Peptide SVVYGLR Improves Cardiac Function in Failing Hearts

AIMS:

Transplantation of myoblast sheets is a promising therapy for enhancing cardiac function after heart failure. We have previously demonstrated that a 7-amino-acid sequence (Ser-Val-Val-Tyr-Gly-Leu-Arg) derived from osteopontin (SV peptide) induces angiogenesis. In this study, we evaluated the long-term therapeutic effects of myoblast sheets secreting SV in a rat infarction model.

METHODS AND RESULTS:

Two weeks after ligation of the left anterior descending coronary artery, the animals were divided into the following three groups: a group transplanted with wild-type rat skeletal myoblast sheets (WT-rSkMs); a group transplanted with SV-secreting myoblast sheets (SV-rSkMs); and a control group (ligation only). We evaluated cardiac function, histological changes, and smooth muscle actin (SMA) expression through transforming growth factor-β (TGF-β) signalling. The ejection fraction and fractional shortening were significantly better, and the enlargement of end-systolic volume was also significantly attenuated in the SV-rSkM group. Left ventricular remodelling, including fibrosis and hypertrophy, was significantly attenuated in the SV-rSkM group, and SV secreted by the myoblast sheets promoted angiogenesis in the infarcted border area. Furthermore, many clusters of SMA-positive cells were observed in the infarcted areas in the SV-rSkM group. In vitro SMA expression was increased when SV was added to the isolated myocardial fibroblasts. Moreover, SV bound to the TGF-β receptor, and SV treatment activated TGF-β receptor-Smad signalling.

CONCLUSION:

The SV-secreting myoblast sheets facilitate a long-term improvement in cardiac function. The SV can induce differentiation of fibroblasts to myofibroblasts via TGF-β-Smad signalling. This peptide could possibly be used as a bridge to heart transplantation or as an ideal peptide drug for cardiac regeneration therapy.