Pancreatic epithelial progenitor cells differentiate into mature hepatocytes following transplantation into the rat liver

Recently, we reported the existence of epithelial progenitor cells in tue rat pancreas that can be induced during dietary Cu deficiency to proliferate and express liver-specific genes (Am. I. Pathol. HI: 1633-1648, 1995). To determine whether these cells have the potential to differentiate into mature hepatocytes, we used a cell transplantation strategy in which pancreatic epithelial cells from inbred Fischer 344 rats that express dipetidyl peptidase IV (DPPiy) are transplanted to the liver of a DPP1V mutant strain of Fischer 344 rats. Pancreatic epithelial cells, activated by Cu deficiency as previously reported, were isolated by collagenase perfusion followed by Nycodenz gradient ccntrifugation, and 1 x 106 cells were transplanted to the liver via the portal vein. After 1-3 months, DPPIV cells were observed in two morphologic configurations: 1) small epithelial cells arranged in duct-like structures and 2) cells arranged in clusters with a much larger, round shaped nucleus and expanded eosinophilic cytoplasm, reminiscent of hepatocytes. Transplanted cells in duct-like structures expressed DPPIV diffusely over the cell surface, whereas transplanted cells with an hepatpcyte-like morphology expressed DPPIV in a bile canalicular distribution. Dual histochemistry for DPPIV and ATPase (another bile canalicular marker) showed physical continuity between transplanted cells and endogenous hepatocytes within the liver plates. Double label fluorescent confocal laser scanning microscopy showed simultaneous expression of DPPPV and albumin in cells with an hepatocyte-like morphology, providing definitive evidence that after transplantation, pancreatic epithelial progenitor cells can differentiate into mature hepatocytes and fully integrate into the liver parenchyma. These findings raise the possibility that further study of progenitor cells will provide insights into liver repopulation and possible treatment of fulminant liver failure or chronic liver disease via cell transplantation, as well as the potential use of these cells for somatic gene therapy.