Inter-organ transmission of hepatocellular senescence induces multi-organ dysfunction through the TGFβ signalling pathway.

Abstract Cellular senescence is associated with aging but also impacts various physiological and pathological processes such as embryonic development and wound healing. Factors secreted by senescent cells can affect their microenvironment, including local spreading of senescence. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here, using genetic mouse models of hepatocyte-specific senescence, we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence. Additionally, we observe senescence-associated regeneration and reprogramming in the proximal tubules of the kidney. Using single cell transcriptomics and in vitro assays, we identify the Transforming Growth Factor β (TGFβ) pathway as a critical mediator of systemic spread of senescence. Lastly, TGFβ inhibition in our mouse models blocks senescence transmission to other organs and prevents renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence which, independent of aging, contributes to multi-organ dysfunction.