Biomimetic mineralized microenvironment stiffness regulated BMSCs osteogenic differentiation through cytoskeleton mediated mechanical signaling transduction.

Construction of biomimetic microenvironment is vital to understand the relationship between matrix mechanical cues and cell fate, as well as to explore potential tissue engineering scaffolds for clinical application. In this study, through the enzymatic mineralizable collagen hydrogel system, we established the biomimetic bone matrix which was capable of realizing mechanical regulation independent of mineralization by incorporation of phosphorylated molecules (vinylphosphonic acid, VAP). Then, based on the biomimetic mineralized matrix with same composition but significantly different mechanical stiffness, we further investigated the effect of matrix stiffness on osteogenic differentiation of bone marrow stromal cells (BMSCs). The results clearly demonstrated that biomimetic mineralized microenvironment with higher mechanical strength promoted osteogenic differentiation of BMSCs. Further mechanism analysis demonstrated that the mineralized hydrogel with higher stiffness promoted cytoskeletal assembly, which enhanced the expression and nuclear colocalization of YAP and RUNX2, thereby promoted the osteogenic differentiation of stem cells. This study supplies a promising material platform not only for bone tissue engineering but also for exploring the mechanism of biomimetic bone matrix mechanics on osteogenesis.