Dynamic regulation of myofibroblast phenotype in cellular senescence

Cellular senescence is an antiproliferative response with a critical role in the control of cellular balance in diverse physiological and pathological settings. Here, we set to study the impact of senescence on the regulation of cell plasticity, focusing on the regulation of the myofibroblastic phenotype in primary fibroblasts. Myofibroblasts are contractile, highly fibrogenic cells with key roles in wound healing and fibrosis. Using cellular models of fibroblast senescence, we find a consistent loss of myofibroblastic markers and functional features upon senescence implementation. This phenotype can be transmitted in a paracrine manner, most likely through soluble secreted factors. A dynamic transcriptomic analysis during paracrine senescence confirmed the non-cell-autonomous transmission of this phenotype. Moreover, gene expression data combined with pharmacological and genetic manipulations of the major SASP signaling pathways suggest that the changes in myofibroblast phenotype are mainly mediated by the Notch/TGF-beta axis, involving a dynamic switch in the TGF-beta pathway. Our results reveal a novel link between senescence and myofibroblastic differentiation with potential implications in the physiological and pathological functions of myofibroblasts.

Automated summary

Cellular senescence has a significant impact on the regulation of the myofibroblastic phenotype in primary fibroblasts. The loss of myofibroblastic markers and functional features upon senescence implementation can be transmitted in a paracrine manner, most likely through soluble secreted factors. The Notch/TGF-beta axis is found to be the main pathway mediating the changes in the myofibroblast phenotype.