p21 (Cdkn1a) Regulates Senescent Cell Viability and Lung Fibrosis

Cellular senescence is a stable state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. However, accumulation of senescent cells in tissues during aging contributes to age-related pathologies. The CDK inhibitor p21 (Cdkn1a) maintains the viability of DNA damage-induced senescent cells. Furthermore, p21 regulates the expression of ECM (extracellular martix) components that contribute to the development of age related fibrotic diseases. Here we study the role of p21 in-vitro and in-vivo, using a new inducible p21 knockdown mouse model. We revealed that p21 knockdown in senescent cells, in culture, leads to a CDK4-dependent decrease in collagen expression. In-vivo, p21 knockdown in Bleomycin-induced lung fibrosis leads to a reduction in expression of senescence markers, and to a decrease in the inflammatory response. Moreover, p21 knockdown leads to an alleviation in the lung fibrosis pathology and to a reduction in collagen expression. Overall, these findings show that p21 regulates senescent cell viability and fibrosis.