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恶性肝肿瘤的唯一根治性治疗选择。特别是扩大切除需要肝脏的高再生潜力。如果肝残体的再生和代谢功能被超过，可能会出现急性术后肝功能衰竭，这与高死亡率风险相关。原则上，肝切除高达70%的健康肝脏是可行的，没有器官衰竭的风险。然而，如果肝实质已经被先前存在的疾病如NASH、ASH或CASH损害，则风险急剧增加，这些疾病会降低残余物的代谢和再生功能。我们在大鼠和猪的临床相关大型动物模型中的实验研究表明，间充质基质细胞（MSC）提高了剩余肝脏的再生能力，从而改善了术后肝衰竭的风险。我们证明MSC对肝功能的改善是由于血小板反应蛋白-1/TGF-β信号链的抑制。MSC治疗降低了术后血小板反应蛋白-1（THBS 1）的血清水平。然而，THBS 1的全身来源以及MSC如何调节合成和/或分泌是未知的。在我们的猪模型中，MSC治疗显著改善了循环维持。因此，我们假设MSC改善了手术诱导的血流变化，从而抑制了内皮细胞和/或血小板（THBS 1的主要来源）中潜在的剪切应力诱导的THBS 1合成/分泌。该项目的目标是在THBS 1基因敲除小鼠模型中以及在MSC和内皮细胞以及血小板的体外共培养物中调查和确认这种关系。临床上，THBS 1已经被确定为扩大肝脏手术后结果的阴性预测因子。因此，我们的进一步目标是验证扩大的肝切除对THBS 1/TGF-β通路的影响，如在我们的动物模型中在招募接受ALPPS切除的患者的临床研究中所鉴定的，以描绘与手术后多器官损伤的关系，所述手术后多器官损伤以ALPPS切除后的肝肾综合征为例，并因此证实THBS 1是在扩大的肝切除术后MSC治疗的预期临床建立的潜在靶点。

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.