The role of hepatocyte senescence in tissue injury and regeneration in acute-on-chronic liver failure

• Applicant: Privatdozent Dr. Cornelius Engelmann
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527214263

The acute-on-chronic liver failure (ACLF) is a devastating disease which develops on the basis of an acute decompensated liver cirrhosis with extrahepatic organ failures and poor prognosis. The sudden disease worsening is frequently triggered by bacterial infections or other precipitating events which are known to be more harmful when liver cirrhosis is present. This organ sensitization of the liver is the initiating mechanism for ACLF. Furthermore, ACLF is potentially linked to a lack of tissue regeneration which minimizes patients’ prognosis. Hepatocellular senescence, which describes a cell cycle arrest in hepatocytes, might explain both observations as it alters the phenotype and receptor expression in hepatocytes on the one hand and the ability for cellular proliferation and replacement of injured tissue on the other hand. The main aim of this project will be to explore the role of hepatocellular senescence in modulating the course of ACLF. As a first step, human liver tissue from patients with different severity grades of end-stage liver disease will be characterised for the expression and activation of regeneration and senescent pathways. Focus will be on the Mdm2-p53 pathway, which is the classical and most well known senescence pathway. We also hypothesis may be spread in the tissue by TGF-β1 dependent mechanisms. The effect of targeted molecule silencing in vitro (e.g. GapmeRs) and in vivo (e.g. conditional knockout mice) allows to delineate the relevance of individual senescence pathways in ACLF. In vitro studies on 2D cultured hepatocytes and hepatocyte organoids will allow to select the most effective agents for in vivo experiments. Therefore, this project will combine basic and translational science in order to understand the mechanism of regenerative response in ACLF, to develop new experimental techniques and also to pave the way for a novel treatment for a disease with persistent poor prognosis.

• DFG Programme: Research Grants