BPS2026 – Matrix stiffness drives cellular senescence through disruption of nuclear architecture and chromatin remodeling

Cellular senescence limits regenerative capacity, compromises stem-cell function, and disrupts tissue homeostasis. It is a defining hallmark of aging and is further intensified in pathological contexts where extracellular matrices become abnormally stiff and remodel tissue architecture. Both during in vitro expansion and in vivo aging, senescence drives a progressive decline in proliferative capacity and alterations in nuclear architecture. While senescence has been linked to nuclear and chromatin alterations, the mechanistic coupling between extracellular stiffness, nuclear mechanics, and chromatin state remains poorly defined. Here, we demonstrated that substrate stiffness regulates senescence through a chromatin-mechanical axis. Human mesenchymal stem cells cultured on stiff substrates exhibited accelerated senescence, while soft substrates delay it. Direct chromatin remodeling confirmed causality, HAT inhibition-induced chromatin condensation shows reduced senescence on stiff substrates, while HDAC inhibition-induced decondensation exhibits accelerated senescence on soft substrates. Stiff substrate triggered DNA damage, nuclear wrinkling, higher actomyosin contractility, lamin A/B disorganization, and nuclear pore irregularities, while super-resolution STORM imaging revealed reduced lamin B1, loss of lamin-associated domains, and increased heterochromatin foci. In contrast, soft substrates preserved nuclear architecture and chromatin integrity, mitigating senescence. Extending these findings to aging, fibroblasts from older donors mirrored senescent phenotypes, and young fibroblasts when cultured on stiff matrices rapidly acquired aged phenotype including DNA damage, nuclear wrinkling, LADs detachment, and pore irregularities, whereas soft matrices delayed these features. Altogether, these results are consolidated by our analytical model identifying a self-reinforcing feedback loop in which extracellular stiffness reshapes nuclear architecture and chromatin to drive senescence. By establishing nuclear architecture, chromatin condensation, and lamina integrity as central regulators of stiffness-induced senescence, our study uncovers a mechanistic link between extracellular mechanics and aging phenotypes, suggesting therapeutic opportunities to preserve stem cell function and improve regenerative outcomes.