Experimental and clinical proof-of-concept to establish stem cell treatment of post-hepatectomy liver failure

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Extended liver resections are often the only curative therapy option to treat primary and secondary malignant liver tumors. Especially extended resections require a high regenerative potential of the liver. If regenerative and metabolic functions of the liver remnant are exceeded, acute post-operative liver failure may emerge, which is associated with a high mortality risk.Principally, liver resections for up to 70% of the healthy liver are feasible without risk of organ failure. The risk, however, increases dramatically, if the liver parenchyma is already damaged by pre-existing diseases like NASH, ASH, or CASH, which reduce metabolic and regenerative functions of the remnant. We have shown in our experimental studies in the rat and in the clinically relevant large animal model of the pig that mesenchymal stromal cells (MSC) improved the regenerative capacity of the remaining liver, and hence ameliorated the risk of post-operative liver failure. We demonstrated that the improvement of liver function by the MSC was due to the inhibition of the thrombospondin-1/TGF-ß signal chain. MSC treatment reduced post-operative serum levels of Thrombospondin-1 (THBS1). It is, however, unknown, which is the systemic source of THBS1, and how synthesis and/or secretion are regulated by MSC.In our pig model, MSC treatment improved circulatory maintenance significantly. Therefore, it is our hypothesis that the MSC ameliorated surgery-induced changes in blood flow, and hence inhibited the potentially shear stress-induced THBS1 synthesis/secretion in endothelial cells and/or thrombocytes, the major sources of THBS1. It is the goal of the project to investigate and confirm this relationship in a THBS1-knockout mouse model and in vitro in co-cultures of MSC and endothelial cells as well as thrombocytes.Clinically, THBS1 has already been identified as a negative predictor of the outcome after extended liver surgery. Therefore, it is further our goal to validate the impact of extended liver resection on the THBS1/TGF-ß pathway as identified in our animal model in a clinical study enrolling patients undergoing ALPPS resections, to delineate the relationship with post-surgery multi-organ damage exemplified by the hepatorenal syndrome after ALPPS resection, and hence to confirm THBS1 as potential target for the intended clinical establishment of MSC therapy after extended liver resection.