The transplantation of myogenic cells which include muscle derived stem cells (MDSCs), satellite cells, and myoblasts, has been employed due to its ability to present/implant the dystrophin gene into the dystrophic skeletal muscle of Duchenne Muscular Dystrophy (DMD) patients. However, the transient lifespan and poor migration of these donor cells following transplantation, has limited its success. The pathology of significant fibrous scar tissue formation in these patients has a major impact on the capacity for muscle cell regeneration. Specifically, the fibrous scar tissue physically impedes the formation of normal muscle fibers in the injured and diseased muscle, resulting in reduction of myogenic cell migration, fusion and regeneration that ultimately causes the failure of myogenic cell transplantation. A more advantageous strategic approach may be to eliminate the existing fibrous scar in the dystrophic muscle in order to remove the barriers to muscle cell regeneration. Matrix metalloproteinase type 1 (MMP1), a collagen-digesting enzyme has demonstrated the capacity to do just this, as it has shown the ability to digest fibrous scars in different tissues, and could provide pathways to enhance cell migration. The goal of the proposed project is to investigate whether MMP1 can refashion a microenvironment that can then facilitate muscle cell migration, fusion, and regeneration after either direct transplantation or systemic delivery of myogenic cells. This would, we feel, enable accelerated muscle healing in MDX mice, a mouse model of skeletal muscle dystrophin deficiency. The proposed project will study the efficacy of MMP1 in muscle cells (myogenic and fibrotic cells) in vitro as well as the ability to enhance myogenic cell transplantation in the skeletal muscle of MDX mice in vivo. Specifically, we will examine whether MMP1 gene transfer can improve systemic delivery of myogenic cells into dystrophic skeletal muscle of MDX mice. If successful, we expect that this approach would increase the clinical applicability of myogenic transplantation therapy.
