Dynamic hydrogels orchestrate the differentiation fate of mesenchymal stem cells through epigenetic regulation of SETD7 to accelerate bone defect repair.

Dynamic mechanical signaling of the extracellular matrix is a key determinant of mesenchymal stem cell (MSC) fate, closely regulating their proliferation, differentiation and migration. Previously, we developed a highly cell-adaptive dynamic hydrogel (HA-ADA) that modulates MSC fate through unknown mechanisms. Here, using human bone marrow-derived mesenchymal stem cells (hMSCs), we found that sustained mechanical stimulation provided by HA-ADA hydrogel induced rapid spreading and significantly enhanced their osteogenic differentiation while inhibiting adipogenesis. Mechanistically, miRNA sequencing revealed that this process was mediated by the downregulation of miR-376a-3p and miR-127-5p, thereby relieving their inhibitory effect on the methyltransferase SETD7. Elevated SETD7 expression catalyzed methylation of β-catenin and accelerated its nuclear translocation. In the nucleus, β-catenin further formed a transcriptional complex with YAP to synergistically amplify downstream signals and potently activate the expression of Runx2, a key transcription factor for osteogenesis, which ultimately drove osteogenic differentiation and inhibited adipogenesis. The present study elucidated a novel mechanism by which cell-adaptive hydrogels regulate the β-catenin/YAP signaling loop through the miR-376a-3p/miR-127-5p-SETD7 axis, thereby determining the osteogenic/adipogenic differentiation of stem cells, which not only deepens our understanding of mechanotransduction but also provides new targets and material design strategies for bone regeneration.