Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

• Published in: Nature communications Vol. 9; no. 1; pp. 1020 - 15
• Main Authors: Ferreira-Gonzalez, Sofia, Lu, Wei-Yu, Raven, Alexander, Dwyer, Benjamin, Man, Tak Yung, O’Duibhir, Eoghan, Lewis, Philip J. Starkey, Campana, Lara, Kendall, Tim J., Bird, Thomas G., Tarrats, Nuria, Acosta, Juan-Carlos, Boulter, Luke, Forbes, Stuart J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/2; 13/51; 14/1; 14/19; 14/32; 14/63; 38/77; 45/90; 631/80/304; 631/80/509; 64; 64/60; 692/4020/4021/1607/1605; 692/4020/4021/44/1327; 82/80; Animals; Bile ducts; Bile Ducts - injuries; Bile Ducts - pathology; Cell cycle; Cells, Cultured; Cellular Senescence - physiology; Cholangitis, Sclerosing - pathology; Cholangitis, Sclerosing - therapy; Clonal deletion; Collagen; Collagen - metabolism; Disease control; Disease Models, Animal; Female; Gene deletion; Hepatocytes; Hepatocytes - pathology; Humanities and Social Sciences; Humans; Keratin-19 - genetics; Liver; Liver - pathology; Liver Cirrhosis, Biliary - pathology; Liver Cirrhosis, Biliary - therapy; Macrophages; Macrophages - metabolism; Male; MDM2 protein; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Myofibroblasts - metabolism; Paracrine signalling; Proto-Oncogene Proteins c-mdm2 - genetics; Regeneration; Regeneration - physiology; Rodents; Science; Science (multidisciplinary); Senescence; Therapeutic applications; Transforming Growth Factor beta1 - antagonists & inhibitors; Transforming Growth Factor beta1 - metabolism; Viability
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03299-5

Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies. Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies.