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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月30日

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  • Qiangjun Ling,
  • Hao Li,
  • Jianyang Zhao,
  • Weitang Guo,
  • Hong Yu,
  • Zhuo Li,
  • Yuan Hu,
  • Shuzhen Wei,
  • Yiben Fu,
  • Yu Zhang,
  • Kunyu Zhang,
  • Liming Bian

摘要

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.