Laminin Alpha 2-Secreting Fibroblasts Enhance The Therapeutic Effect Of Skeletal Myoblast Sheets

OBJECTIVES: Skeletal myoblast sheet (SMB) transplantation, a method used for treating failing hearts, results in the secretion of cytokines that improve heart function. Enhancing the survival rate of implanted myoblasts should yield more continuous and effective therapies. We hypothesized that laminin-211 (merosin), a major component of skeletal muscle extracellular matrix (ECM), which mediates cell-to-ECM adhesion by binding to alpha-dystroglycan (alpha DG) on muscle cells, could inhibit detachment of implanted myoblasts from host myocardia.METHODS: Multilayered sheets composed of fibroblasts expressing laminin G-module (LG) 4-5 of a2 and skeletal myoblasts were transplanted into ischemic cardiomyopathy model rats. Animals were divided into four groups: the ligation only (Control) group, and those transplanted with SMB alone, with both myoblasts and control fibroblast sheets (SMB + normal Fb), or with myoblasts and laminin a2 LG45- expressing fibroblast sheets (SMB + laminin Fb).RESULTS: Quantitative estimation of nebulin mRNA levels indicated that the transplanted myoblasts in SMB + laminin Fb group exhibited significantly higher survival rates than those in the other groups. Consistent with these findings, the myoblasts in SMB + laminin Fb group exhibited elevated expression of growth factors, while SMB + laminin Fb rats also showed significant improvements in percent fractional shortening (% FS) and left ventricular remodelling, compared to the other groups.CONCLUSIONS: Laminin secreted by implanted fibroblasts inhibited the detachment of implanted myoblasts from grafted myocardia, resulting in more permanent therapeutic effects upon myoblast sheet transplantation.