Proliferation and differentiation of fetal liver epithelial progenitor cells after transplantation into adult rat liver

To identify cells that have the ability to proliferate and differentiate in to all epithelial components of the liver lobule, we isolated fetal Liver e pithelial cells (FLEC) from ED 14 Fischer (F) 344 rats and transplanted the se cells in conjunction with two-thirds partial hepatectomy into the liver of normal and retrorsine (Rs) treated syngeneic dipeptidyl peptidase IV mut ant (DPPIV-) F344 rats, Using dual label immunohistochemistry/in situ hybri dization, three subpopulations of FLEC were identified: cells expressing bo th alpha-fetoprotein (AFP) and albumin, but not CK-19; cells expressing CK- 19, but not AFP or albumin, and cells expressing AFP, albumin, and cytokera tins-19 (CK-19), Proliferation, differentiation, and expansion of transplan ted FLEC differed significantly in the two models. In normal liver, 1 to 2 weeks after transplantation, mainly cells with a single phenotype, hepatocy tic (expressing AFP and albumin) or bile ductular (expressing only CK-19), had proliferated. In Rs-treated rats, in which the proliferative capacity o f endogenous hepatocytes is impaired, transplanted cells showed mainly a du al phenotype (expressing both AFP/albumin and CK-19), One month after trans plantation, DPPIV+ FLEC engrafted into the parenchyma exhibited an hepatocy tic phenotype and generated new hepatic cord structures. FLEC, localized in the vicinity of bile ducts, exhibited a biliary epithelial phenotype and f ormed new bile duct structures or were incorporated into pre-existing bile ducts. In the absence of a proliferative stimulus, ED 14 FLEC did not proli ferate or differentiate. Our results demonstrate that 14-day fetal liver co ntains lineage committed (unipotential) and uncommitted (bipotential) proge nitor cells exerting different repopulating capacities, which are affected by the proliferative status of the recipient liver and the host site within the liver where the transplanted cells become engrafted. These findings ha ve important implications in future studies directed toward liver repopulat ion and ex vivo gene therapy.