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

扩大肝切除术通常是治疗原发性和继发性肝脏恶性肿瘤的唯一治疗选择。尤其是扩大切除需要很高的肝脏再生潜力。如果残肝的再生和代谢功能被超过，可能会出现术后急性肝功能衰竭，这与高死亡率相关。原则上，切除高达70%的健康肝脏是可行的，没有器官衰竭的风险。然而，如果肝实质已经被NASH、ASH或CASH等先前存在的疾病破坏，风险就会急剧增加，这些疾病会降低残留物的代谢和再生功能。我们在大鼠和临床相关的大型动物模型中的实验研究表明，间充质基质细胞(MSC)改善了剩余肝脏的再生能力，从而改善了术后肝功能衰竭的风险。我们证明，MSC改善肝功能是由于抑制了凝血酶反应蛋白-1/转化生长因子-β信号链。MSC治疗可降低术后血清凝血酶敏感蛋白-1(THBS1)水平。然而，目前尚不清楚THBS1的系统来源是什么，以及MSC是如何调节合成和/或分泌的。在我们的猪模型中，MSC治疗显著改善了循环维护。因此，我们的假设是，MSC改善了手术引起的血流变化，从而抑制了潜在的切应力诱导的内皮细胞和/或血小板THBS1的合成/分泌，而内皮细胞和/或血小板是THBS1的主要来源。该项目的目标是在THBS1基因敲除的小鼠模型中，以及在MSC和血管内皮细胞以及血小板的体外共培养中，研究和确认这种关系。临床上，THBS1已经被确定为扩大肝脏手术后预后的负面预测因子。因此，我们的进一步目标是在我们的动物模型中确认扩大肝切除对THBS1/转化生长因子-β通路的影响，以描述与ALPPS切除后肝肾综合征等术后多器官损害的关系，从而确认THBS1作为扩大肝切除后MSC治疗的潜在靶点。

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.