Alcoholic Liver Diseases: Damage, Repair and Stem Cell Regeneration

描述(由申请人提供)：我们已经发现在正常宿主中快速再生的小(50%)肝脏移植在接受长期酒精喂养的宿主中未能做到这一点，并假设慢性酒精滥用的系统影响的一部分是对肝外祖细胞的损害。事实上，在酒精喂养五周后，c-Kit和CXCR4染色的骨髓细胞数量明显减少，这些细胞含有8-OHdG，DNA的稳定氧化加合物。有趣的是，将酒精喂养的大鼠的小肝脏移植到正常大鼠身上时，整个肝脏功能良好，这表明当宿主正常时，来自受损小肝脏的再生信号足以挽救移植物。负责干细胞招募的信息必须存在于暴露于酒精的肝脏中。事实上，血液中IL-6的水平和组织中基质细胞衍生因子-1(SDF-1)的水平都被发现是正常的。成功或失败的细胞机制的描述将通过已建立的标记、绿色荧光蛋白(GFP)转基因Lewis大鼠、Y染色体探针以及Lewis到DA移植的同种抗体进行评估。我们将对酒精性肝病动物和胆总管结扎者进行比较。在这两种类型的肝脏损伤后，干细胞异常的暂时出现，以及差异的大小将有助于区分酒精对干细胞的直接毒性影响，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。这项建议的目的是将孙兆力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起来，作为一个发挥作用的协作单位，开发基于肝外祖细胞活力检测的创新疗法。此外，这些研究有望更好地应用于脂肪肝的移植。这项合作提案将为肝外干细胞/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)是导致肝硬变的最常见原因之一，也是肝移植的适应症。描绘和澄清乙醇如何影响肝脏干细胞/祖细胞，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著增加器官捐赠者的数量。

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.