Mechanical stretch induces osteogenesis through the alternative activation of macrophages

For reconstructive surgeons, critically skeletal damage represents a major challenge. Growing evidence indicate that bone repair is dynamically regulated by the mesenchymal stem cell (MSC)-macrophage interaction. Mechanical strain plays a fundamental role in bone repair and regeneration by influencing MSCs differentiation. Recently, a few findings indicate that macrophages may be mechanically sensitive and their phenotype can be regulated, in part, by mechanical cues. However, how macrophages subjected mechanical stretch influence the osteogenic differentiation of MSCs remain unclear. Thus, the purpose of this study is to explore the effect of macrophages stimulated with mechanical stretch on MSCs osteogenesis. By using a coculture system, we discover that macrophages efficiently induce osteogenic differentiation of MSCs under specific stretch conditions. A synergy mechanism between M2 polarization and YAP/BMP2 axis are identified through molecular and genetic analyses. Macrophages are activated by cyclic stretch and polarized to M2 phenotype that produce anti-inflammatory cytokines such as IL-10 and TGF-β to regulate the local inflammatory microenvironment. Furthermore, mechanical stretch induces YAP activation and nuclear translocation, subsequently regulates downstream BMP2 expression to facilitate MSCs osteogenesis. These findings not only advance our understanding of the complex influence among the mechanical strain, macrophage inflammatory response as well as the osteogenic differentiation of MSCs, but also reveal a control system from mechanical signals to chemical response then to cell behaviors during bone repair and regeneration.