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<p>Cellular senescence significantly impairs tissue repair through disrupting tissue homeostasis and limiting regenerative capacity. Biomaterial based microenvironment modulation has emerged as a promising strategy to counteract senescence and promote tissue regeneration. While mechanical properties such as matrix stiffness are known to influence cell fate, whether different tissue-derived cells exhibit distinct mechanical requirements for senescence resistance remains poorly understood. Here, we used stiffness-tunable polyacrylamide hydrogels spanning physiologically relevant elastic moduli and systematically evaluated senescence responses in neuronal (SH-SY5Y), dermal fibroblast (NIH3T3), and osteoblast precursor (MC3T3-E1) cells. Our results revealed tissue-specific stiffness windows that maximally suppressed senescence, with optimal senescence resistance responses observed at 1&#xa0;kPa, 10&#xa0;kPa, and 250&#xa0;kPa for SH-SY5Y, NIH3T3, and MC3T3-E1 cells, respectively. Mechanistically, integrin α1, a collagen-binding integrin, was identified as a key mechanosensor mediating these effects. Optimal stiffness conditions enhanced integrin α1-mediated mechanotransduction, cytoskeletal remodeling, and activation of PI3K–Akt and YAP signaling pathways, leading to the downregulation of senescence markers (p16, p21) and upregulation of proliferation related genes. These findings provide a mechanistic framework for the design of stiffness-matched biomaterials to counteract senescence and enhance tissue regeneration.</p> Graphical Abstract <p></p>

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Tissue-specific regulation of cellular senescence on elastic hydrogels via the integrin α1-mediated mechanotransduction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Limin Song,
  • Xinying Wang,
  • Yiyao Pu,
  • Xueyi Hu,
  • Jing He,
  • Rongrong Jin,
  • Yu Nie

摘要

Cellular senescence significantly impairs tissue repair through disrupting tissue homeostasis and limiting regenerative capacity. Biomaterial based microenvironment modulation has emerged as a promising strategy to counteract senescence and promote tissue regeneration. While mechanical properties such as matrix stiffness are known to influence cell fate, whether different tissue-derived cells exhibit distinct mechanical requirements for senescence resistance remains poorly understood. Here, we used stiffness-tunable polyacrylamide hydrogels spanning physiologically relevant elastic moduli and systematically evaluated senescence responses in neuronal (SH-SY5Y), dermal fibroblast (NIH3T3), and osteoblast precursor (MC3T3-E1) cells. Our results revealed tissue-specific stiffness windows that maximally suppressed senescence, with optimal senescence resistance responses observed at 1 kPa, 10 kPa, and 250 kPa for SH-SY5Y, NIH3T3, and MC3T3-E1 cells, respectively. Mechanistically, integrin α1, a collagen-binding integrin, was identified as a key mechanosensor mediating these effects. Optimal stiffness conditions enhanced integrin α1-mediated mechanotransduction, cytoskeletal remodeling, and activation of PI3K–Akt and YAP signaling pathways, leading to the downregulation of senescence markers (p16, p21) and upregulation of proliferation related genes. These findings provide a mechanistic framework for the design of stiffness-matched biomaterials to counteract senescence and enhance tissue regeneration.

Graphical Abstract