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.