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The dynamic mechanical signal transmission of the extracellular matrix is a key determinant of the fate of mesenchymal stem cells (MSCs), closely regulating their proliferation, differentiation, and migration. Previously, we developed a highly cell-adaptive dynamic hydrogel (HA-ADA) that regulates the fate of MSCs through an unknown mechanism. Using human bone marrow-derived mesenchymal stem cells (hMSCs), we found that the continuous mechanical stimulation provided by the HA-ADA hydrogel can induce rapid diffusion, significantly enhance their osteogenic differentiation, and simultaneously inhibit adipogenic differentiation. Mechanistically, miRNA sequencing revealed that this process is mediated by the downregulation of miR-376a-3p and miR-127-5p, thereby reducing their inhibitory effect on the methyltransferase SETD7. The increased expression of SETD7 catalyzes the methylation of β-chain protein and accelerates its nuclear translocation. In the cell nucleus, β-catenin further forms a transcriptional complex with YAP, synergistically amplifying downstream signals and strongly activating the expression of Runx2, which is a key transcription factor for bone formation and ultimately drives bone formation differentiation and inhibits adipogenic differentiation. This study elucidates a new mechanism by which the cell-adaptive hydrogel regulates the β-chain protein/YAP signaling loop through the epigenetic regulation of SETD7 to accelerate bone defect repair, thereby determining the osteogenic/adipogenic differentiation of stem cells. This not only deepens our understanding of mechanical transduction but also provides new targets and material design strategies for bone regeneration.
This study was published in Bioactive Materials under the title "Dynamic hydrogels orchestrate the differentiation fate of mesenchymal stem cells through epigenetic regulation of SETD7 to accelerate bone defect repair".
Reference: DOI: 10.1016/j.bioactmat.2026.01.019
