Host senescence determines the success of hepatocyte transplantation in a mouse model of liver injury
Hepatocyte transplantation has shown promise for genetic diseases but has mixed efficacy for acute and severe liver injury. Limited cell engraftment and poor function of donor hepatocytes in recipient liver are significant hurdles for clinical efficacy. Hepatocyte senescence is a key feature of many liver diseases. Senescence-driven liver injury could be induced in Ahcre+Mdm2fl/fl mice in controlled and predictable levels through excision of hepatocyte Mdm2. Host senescence and injury was a requirement for initial donor hepatocyte engraftment and repopulation, but too much was inhibitory to this. Long-term expansion of transplanted hepatocytes improved histological features of injury and liver function. However graft function could spontaneously decline due to transmission of senescence from host to donor cells. Modification of the host niche prior to transplantation with senotherapeutic drug ABT737 improved donor cell proliferative capacity. Targeting paracrine senescence may be a way to improve donor hepatocyte function, optimise therapy and guide translation into the clinics. Overall design: Differential expression between hepatocytes isolated from induced AhCre+Mdm2fl/fl (senescent) [n=3] and healthy control (AhCre-) mice [n=3]