Mechanical Stretch Upregulates SDF-1α in Skin Tissue and Induces Migration of Circulating Bone Marrow-Derived Stem Cells into the Expanded Skin

Background: Skin and soft tissue expansion is a procedure that stimulates skin regeneration by applying continuous mechanical stretching of normal donor skin for reconstruction purposes. We have reported that topical transplantation of bone marrow-derived mesenchymal stem cells (MSCs) can accelerate mechanical stretch induced skin regeneration. However, it is unclear how circulating MSCs respond to mechanical stretch in skin tissue. Methods: MSCs from luciferase-Tg Lewis rats were transplanted into a rat tissue expansion model and tracked in vivo by luminescence imaging. Expression levels of chemokines including macrophage inflammatory protein-1, thymus and activation-regulated chemokine, secondary lymphoid tissue chemokine, cutaneous T-cell attracting chemokine, and stromal-derived factor-1 (SDF-1) were elevated in mechanically stretched tissues, as were their related chemokine receptors in MSCs. Chemotactic assays were conducted in vitro and in vivo to assess the impact of chemokine expression on MSC migration. Results: MSC migration was observed in mechanically stretched skin. Mechanical stretching induced temporal upregulation of chemokine expression. Among all the tested chemokines, SDF-1 showed the most significant increase in stretched skin, suggesting a strong connection to migration of MSCs. The in vitro chemotactic assay showed that conditioned medium from mechanically stretched cells induced MSC migration, which could be blocked with the CXCR4 antagonist AMD3100, as effectively as medium containing 50 ng/ml rat recombinant SDF-1. Results from in vivo study also showed that MSC migration to mechanically stretched skin was significantly blocked by AMD3100. Moreover, migrating MSCs expressed differentiation markers, suggesting a contribution of MSCs to skin regeneration through differentiation. Conclusion: Mechanical stretching can upregulate SDF-1 in skin and recruit circulating MSCs through the SDF-1/CXCR4 pathway.