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

建立干细胞治疗肝切除术后肝衰竭的实验和临床概念验证

• 批准号: 428832822
• 负责人: Professor Dr. Bruno Christ
• 金额: --
• 依托单位: Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428832822?language=en
• 关键词: Experimental; clinical; proof; concept; establish

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.

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治疗选择。特别是大面积切除需要肝脏有很高的再生潜力。如果肝残体的再生和代谢功能超过，可能出现术后急性肝衰竭，这与高死亡率相关。原则上，切除多达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，则风险会急剧增加，这些疾病会降低残余的代谢和再生功能。我们在大鼠和猪临床相关大型动物模型的实验研究中表明，间充质间质细胞（MSC）提高了剩余肝脏的再生能力，从而降低了术后肝衰竭的风险。我们证明MSC对肝功能的改善是由于抑制血栓反应蛋白-1/TGF-ß信号链。骨髓间充质干细胞治疗降低了术后血清血栓反应蛋白-1 （THBS1）水平。然而，目前尚不清楚THBS1的全身来源是什么，以及MSC如何调节THBS1的合成和/或分泌。在我们的猪模型中，MSC治疗显著改善了循环维持。因此，我们的假设是MSC改善了手术引起的血流变化，从而抑制了内皮细胞和/或血小板中潜在的剪切应力诱导的THBS1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敲除小鼠模型和MSC与内皮细胞以及血小板的体外共培养中调查和确认这种关系。在临床上，THBS1已被确定为长期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一项纳入ALPPS切除术患者的临床研究中验证我们在动物模型中发现的延长肝切除术对THBS1/TGF-ß通路的影响，描述其与ALPPS切除术后肝肾综合征等术后多器官损害的关系，从而确认THBS1是延长肝切除术后MSC治疗的潜在临床建立靶点。