Nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts

Cumulative tension on the nuclear membrane of aortic fibroblasts resulting from increases in the stiffness of the extracellular matrix transforms transiently activated fibroblasts into fibrosis-driving myofibroblasts with condensed chromatin. Fibrotic disease is caused by the continuous deposition of extracellular matrix by persistently activated fibroblasts (also known as myofibroblasts), even after the resolution of the injury. Using fibroblasts from porcine aortic valves cultured on hydrogels that can be softened via exposure to ultraviolet light, here we show that increased extracellular stiffness activates the fibroblasts, and that cumulative tension on the nuclear membrane and increases in the activity of histone deacetylases transform transiently activated fibroblasts into myofibroblasts displaying condensed chromatin with genome-wide alterations. The condensed structure of the myofibroblasts is associated with cytoskeletal stability, as indicated by the inhibition of chromatin condensation and myofibroblast persistence after detachment of the nucleus from the cytoskeleton via the displacement of endogenous nesprins from the nuclear envelope. We also show that the chromatin structure of myofibroblasts from patients with aortic valve stenosis is more condensed than that of myofibroblasts from healthy donors. Our findings suggest that nuclear mechanosensing drives distinct chromatin signatures in persistently activated fibroblasts.

Automated summary

Increased extracellular stiffness activates fibroblasts, leading to the transformation of transiently activated fibroblasts into myofibroblasts with condensed chromatin. The condensed chromatin structure of myofibroblasts is associated with cytoskeletal stability, and nuclear mechanosensing plays a key role in driving distinct chromatin signatures in persistently activated fibroblasts.