Intracellular traction forces modulate chromatin accessibility at the FOXO1 locus
In summary, our study demonstrates that cellular traction forces modulate cellular senescence by promoting chromatin accessibility, particularly at regions associated with FOXO1 expression. This localized chromatin remodeling facilitates FOXO1 activation, which serves as a critical mediator linking cell mechanics to transcriptional and functional changes that regulate senescence. These findings highlight the role of mechanical forces in orchestrating chromatin dynamics and underscore FOXO1 as a key target in the mechanotransduction-mediated regulation of aging. Overall design: Bone marrow aspirates were obtained from patients aged 60–80 years (old group) and 18–30 years (young group). Bone marrow-derived mesenchymal stem cells (BMSCs) were cultured by plating 1 mL of bone marrow into T-75 flasks containing growth medium supplemented with 10% fetal bovine serum (Gibco). BMSCs at passages 1–2 was used for all downstream experiments. To enhance cellular traction forces, senescent BMSCs were seeded onto a stretching device (Cell&Force, Cell Tank, Hangzhou Surface&Force Technology Co., Ltd) and subjected to cyclic mechanical stimulation at 5% strain and 0.02 Hz for 2 h. Conversely, to attenuate traction forces, young BMSCs were cultured on soft hydrogels with a shear modulus of 1.5 kPa for 24 h.