Papel de CXCR4/SDF1 y MMP-10 en regeneración muscular

Résumé

Skeletal muscle is maintained and repaired by the satellite cells, the adult stem cells of muscle located between the basal lamina and the sarcolemma of the muscle fibre. After injury, skeletal muscle degeneration and regeneration occur by a well-characterized process of myofiber necrosis, satellite cell activation and proliferation, myoblast migration and differentiation, and eventual myofiber regeneration. During the regenerative process of muscle, satellite cells must cross the basement membrane of established myofiber and migrate towards the injured area, contributing to the repair of distant fibers. This idea is consistent with the capacity of satellite cells to produce and secrete metalloproteinases (MMPs), a family of proteolytic enzymes that degrade extracellular matrix components, and chemokines, a family of proteins that guide satellite cells to migrate to injured sites. Because satellite cell-derived myoblasts produce MMP-10, and this enzyme degrades a wide variety of extracellular matrix components present in the muscle fibers such as proteoglycans, collagen, laminin and fibronectin, we explored the role of this MMP during muscle regeneration. Furthermore, since satellite cells express CXCR4 and migrate towards SDF1 gradients, we studied the role of the CXCR4/SDF1 axis on the regenerative process of muscle, and its interaction with MMP-10. We have demonstrated that both MMP-10 and CXCR4/SDF1 are necessary for efficient muscle regeneration and we proposed a mechanism by which satellite cells require both systems to regenerate damaged muscle. After injury, skeletal muscle responds by increasing the levels of MMP-10, released by satellite cells or by other cell types present in injured muscle such as monocytes, macrophages or endothelial cells. The presence of activated MMP-10 leads to the increase of VEGF levels but also facilitates the release or activation of SDF1, which in turn, would also modulate the activation of MMP-10. The increase of SDF1, MMP-10 and VEGF levels promotes the regeneration of damaged fibres, improving the ability of satellite cells to proliferate, differentiate and self-renew. Furthermore, the capacity of MMP-10 to degrade collagen IV allows that activated satellite cells of distant fibres, which express CXCR4, cross their basal membrane and migrate toward the increase of SDF1 which is generated in the damaged area. Finally, MMP-10 promotes muscle regeneration by degrading, directly or indirectly, collagen I and III, reducing the appearance of fibrosis which is generated after injury.