Cellular Origins of Regenerating Nodules and Malignancy in the FAH Model of Liver Injury after Bone Marrow Cell Transplantation

In previous reports, we and other groups have shown that proliferating hepatocytes are formed by the fusion of donor hematopoietic cells with host hepatocytes in the Fah(−/−) model. Thus, it would be interesting to determine whether cell fusion occurs during malignancy. However, it is difficult to demonstrate such processes using this model. Therefore, we established a new strain to study the processes of regenerating nodules and malignancy and their origins. The FAH(−/−) mouse model was crossed with the ROSAnZ strain and their offspring was genotyped for FAH(−/−) and ROSAnZ mutations to create a new strain (Fah(−/−)-ROSAnZ). Using this strain as recipients, we performed bone marrow transplantation experiments. As a result, we could not demonstrate the presence of any epithelial cells except hepatocytes that were of donor origin in regenerating tissue, and no evidence of cell fusion was found in tumors. The hepatic malignancy was of host origin in these mice. There was higher expression of extracellular matrix proteins and more inflammatory cells in liver tumor nodules than in regenerating normal liver nodules. Hepatocytes generated by fusion with bone marrow cells did not form malignant tumors. Extracellular matrix and inflammatory cells had significantly accumulated in liver tumors.