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

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 however, the presence of hepatic senescence is associated with poor prognosis and extrahepatic organ failure in acute liver disease. 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. In patients with acute indeterminate hepatitis, the extent of hepatocellular senescence predicts the occurrence of extrahepatic dysfunction, need for liver transplantation and mortality. We identify the Transforming Growth Factor Beta (TGFbeta) pathway as a critical mediator of systemic spread of senescence and TGFbeta inhibition blocks senescence transmission to other organs preventing renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence which, independent of aging, contributes to multi-organ dysfunction. An adeno-associated viral (AAV) vector system is used to express the mutant KRasG12D in the hepatocytes of mice. Bulk RNA-Seq was used to determine the transcriptional differences between control and mutant KRasG12D. 4 AAV8-Cre2 controls, 4 AAV8-Cre2 treatments , 4 AAV8-Cre4 controls, 4 AAV8-Cre4 treatments, and 4 untreated controls from kidney tissue were used. The samples were split over two sequence runs 180804 and 180805. The TruSeq Stranded mRNA kit was used and the samples sequenced on a NextSeq 500. Raw fastq.gz where quality trimmed with FastP and aligned to the GRCm38.92 genome with HiSat2. The reads where summarized using Feature Counts.