Alcoholic Liver Diseases: Damage, Repair and Stem Cell Regeneration

描述（由申请人提供）：我们发现，在正常宿主中快速再生的小（50%）肝移植，在长期饮酒的宿主中不能再生，并假设长期饮酒的全身效应的一部分是肝外祖细胞的损伤。事实上，在五周的酒精喂养后，c-Kit和CXCR 4染色的骨髓细胞数量显著减少，这些细胞含有8-OHdG，DNA的稳定氧化加合物。有趣的是，来自酒精喂养的大鼠的小肝脏移植到正常大鼠中功能良好，而整个肝脏失败，这表明当宿主正常时，来自小受损肝脏的再生信号足以挽救移植物。负责招募干细胞的信息必须存在于暴露于酒精的肝脏中。事实上，发现IL-6的血液水平和基质细胞衍生因子-1（SDF-1）的组织水平正常。将使用已建立的标记、绿色荧光蛋白（GFP）转基因刘易斯大鼠、Y染色体探针和同种抗体（在刘易斯进行DA移植的情况下）评估导致成功或失败的细胞机制的描述。将在患有酒精性肝病的动物和结扎胆总管的动物之间进行比较。这两种类型的肝损伤后干细胞异常的时间表现，以及差异的大小将有助于区分酒精对干细胞的直接毒性作用，以及与肝功能衰竭过程平行的干细胞数量和功能的缓慢丧失。该提案的目的是将孙兆利博士在肝移植模型方面的专业知识和高斌博士在酒精性肝病方面的专业知识结合在一起，以便作为一个运作的合作单位，可以开发基于肝外祖细胞活力检查的创新疗法。此外，这些研究有望在更好地利用脂肪肝进行移植方面找到应用。这项合作计划将为肝外干/祖细胞的作用提供新的见解。 公共卫生相关性：酒精性肝病（ALD）是肝硬化最常见的原因之一，也是肝移植的指征。乙醇如何影响肝干/祖细胞的描述和澄清可能会导致酒精性肝病的新疗法。利用酒精肝进行移植的能力将显着增加器官供体库。

DESCRIPTION (provided by applicant): We have found that a small (50%) liver transplant which regenerates rapidly in a normal host, fails to do so in a host subjected to chronic alcohol feeding and postulate that a part of the systemic effects of chronic alcohol abuse is damage to extra-hepatic progenitor cells. Indeed, after five weeks of alcohol feeding the numbers of bone marrow cells staining for c-Kit and CXCR4 are markedly diminished, and these cells contain 8-OHdG, the stable oxidative adduct of DNA. Interestingly, a small liver from an alcohol fed rat transplanted to a normal rat functions well while a whole liver fails suggesting that regenerative signals from the small damaged liver are sufficient to rescue the graft when the host is normal. The messages responsible for the recruitment of stem cells must be present in the liver exposed to alcohol. Indeed blood levels of IL-6, and tissue levels of stromal cell-derived factor-1 (SDF-1) were found to be normal. Delineation of the cellular mechanisms leading to either success or failure will be assessed with established labels, green fluorescent protein (GFP) transgenic Lewis rats, Y chromosome probes, and alloantibody in the case of Lewis to DA transplants. Comparisons will be made between animals with alcohol liver disease and those with ligation of the common bile duct. The temporal appearance of stem cell abnormalities after these two types of liver insults, and the magnitude of the differences will help distinguish between a direct toxic effect of alcohol on stem cells, and a slow loss of stem cell numbers and function paralleling the course of liver failure. The objective of this proposal is to bring together Dr. Zhaoli Sun's expertise in liver transplantation models and Dr. Bin Gao's expertise in alcoholic liver diseases so that, as a functioning collaborative unit, innovative new therapies based on examinations of extra-hepatic progenitor cell vitality may develop. Further, there is hope that these studies will find application in better usage of the fatty liver for transplantation. This collaborating proposal will provide novel insights into the role of extra-hepatic stem/progenitor cells. PUBLIC HEALTH RELEVANCE: Alcoholic liver disease (ALD) is one of the most common causes of cirrhosis and indication for liver transplantation. Delineation and clarification of how ethanol influences hepatic stem/progenitor cells may lead to new therapies for alcoholic liver disease. The ability to utilize alcoholic livers for transplantation would significantly increase the organ donor pool.