Modulating SPARC expression in mesenchymal stem cells improves MSCs-mediated skin regeneration and wound repair

Mesenchymal stem cells (MSCs) have garnered significant attention over the past three decades due to their robust regenerative potential, primarily mediated through their paracrine activity, involving the release of soluble bioactive factors and extracellular vesicles (EVs). The MSC secretome plays a pivotal role in wound healing by influencing cellular migration, inflammation, angiogenesis, extracellular matrix (ECM) remodeling, and re-epithelialization. SPARC (Secreted Protein Acidic and Rich in Cysteine), a multifunctional ECM glycoprotein involved in tissue repair and remodeling, regulates key processes such as cell migration, proliferation, angiogenesis, and survival. Despite its known role in ECM dynamics, the impact of SPARC expression on the regenerative properties of MSCs remains underexplored. In this study, we hypothesized that SPARC overexpression in MSCs enhances their regenerative capacity. Using lentiviral systems, we generated SPARC-overexpressing (+ SPARC) and SPARC-knockdown (KD-SPARC) MSCs to investigate SPARC's role in wound healing. Conditioned media (CM) derived from these MSCs were analyzed in vitro for their effects on human skin keratinocytes and fibroblasts. Our results revealed that SPARC expression significantly influences cell-specific migration and cell cycle progression. Furthermore, in an in vivo wound healing model, CM from +SPARC MSCs accelerated regeneration, whereas the absence of SPARC in MSC-derived CM delayed the healing process. These findings underscore the critical role of SPARC in modulating MSCs functionality and enhancing the regenerative efficacy of their CM. This study highlights SPARC as a promising therapeutic target for the development of advanced regenerative therapies aimed at improving cutaneous wound healing outcomes.