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

Abstract 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