2008 AFAR Research Grant: Role of Aging in the Mechanism of Liver Repopulation by Transplanted Fetal Liver Stem/Progenitor Cells

Please give a brief summary of your AFAR research project.
In the United States, more then 30,000 people die each year from chronic liver disease. Liver transplantation is the only clinical treatment for this problem. However, due to a severe shortage of liver organ donors, liver researchers are trying to find alternative treatment strategies to replace diseased liver tissue by stem cell transplantation. Over the past several years, we have shown that fetal liver stem cells effectively repopulate the normal liver in a rat model system. More recently, we have discovered that the repopulation level is dramatically increased in older rats compared to younger rats, and extensive repopulation can be achieved in older rats with many fewer transplanted cells. Therefore, in this AFAR research project we are studying the fundamental mechanism by which transplanted fetal liver stem cells show increased ability to repopulate the liver in aging rats.

What problems are you addressing and what specific questions will your research seek to answer?
In previous studies, we discovered that repopulation of the liver occurs as a result of cell competition between transplanted fetal liver stem cells and host hepatocytes. Since the regenerative potential of the liver decreases with age, we believe that the transplanted cells have an increasing advantage over the host hepatocytes in older recipients. To discover the changes during the cell competition process between transplanted and host cells in older vs. younger recipients, we will measure and compare the key factors driving cell competition, such as cell proliferation and cell death.

What aspects of your project are most interesting from a scientific point of view?
We have evidence that senescent hepatocytes, that are not able to proliferate, accumulate in the livers of aging rats. In addition, we are trying to determine whether these senescent hepatocytes are killed by transplanted fetal liver stem cells that are growing very quickly.

What are the implications of your research for age-related diseases and disorders?
If the findings in our studies are applicable to humans, they will have tremendous clinical implications for developing cell therapy strategies to treat chronic liver diseases in the elderly.

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