Mechanically heterogeneous hydrogel with cell-programmed network restructuring promotes tissue regeneration by mechano-epigenetic modulation

Stem cell differentiation dynamically remodels and stiffens the extracellular matrix (ECM), generating stage-specific biomechanical cues that guide tissue development. However, conventional biomaterials, designed to mimic mature ECM stiffness, neglect its spatiotemporal heterogeneity due to their static, non-evolvable nature. Herein, we develop a cell-programmed adaptative contraction (CPAC) hydrogel that enables mesenchymal stem cells (MSCs) to actively remodel their microenvironment through alkaline phosphatase (an early osteogenic marker)-mediated hydrophilic-to-hydrophobic transition and contraction of microgels. This cell-programmed remodeling establishes local mechanical heterogeneity and promotes osteogenesis through a positive feedback loop. Mechanistically, the evolving matrix enhances mechanotransduction-related microRNA expression, suppresses EZH2, and reduces H3K27 trimethylation to active osteogenic transcription. In vivo, MSC-laden CPAC hydrogels significantly enhance the repair of rat cranial defects. These findings introduce a paradigm of cell-instructed, dynamically evolvable biomaterials that recapitulate the adaptive nature of native ECM to orchestrate stem cell fate and tissue morphogenesis. The mechanical microenvironment for MSCs is crucial for osteogenesis. Here, the authors developed a hydrogel in which MSC-secreted ALP actively remodels the surrounding heterogeneous mechanical microenvironment to promote osteogenesis for bone regeneration.