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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA018113-04
Application #
8494464
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Orosz, Andras
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$335,473
Indirect Cost
$130,776
Name
Johns Hopkins University
Department
Surgery
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Okabayashi, T; Cameron, A M; Hisada, M et al. (2011) Mobilization of host stem cells enables long-term liver transplant acceptance in a strongly rejecting rat strain combination. Am J Transplant 11:2046-56
Zhang, Xiuying; Tachibana, Shingo; Wang, Hua et al. (2010) Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. Hepatology 52:2137-47