EVIDENCE FOR A TERMINAL DIFFERENTIATION PROCESS IN THE RAT-LIVER

In rapidly renewing epithelia, such as skin and gut, as well as hemopo ietic cells and stromal fibroblasts, the process of progenitor cell ma turation, terminal differentiation and senescence from cells of a feta l phenotype is strikingly similar. To examine hepatocellular maturatio n, we studied embryonic, suckling and young adult rat liver cells with multiparametric fluorescence activated cell sorting (FAGS), after exc lusion of hemopoietic, endothelial, Kupffer, and nonviable cells. With maturation, cell granularity and autofluorescence exponentially incre ased from fetal liver to suckling and adult liver as the proportion of S phase cells progressively declined from 33.8%+/-1.3% to 4.9%+/-2.8% and 1.1%+/-0.6% (P<0.05), respectively. In liver from fetal and suckl ing rats, all hepatocytes were mononuclear and contained diploid DNA w hereas 21.2%+/-5.9% hepatocytes in adult liver were binucleated. Analy sis of nuclear DNA content in adult hepatocytes demonstrated that 53.3 %+/-3.9% of the nuclei were diploid, 43.6%+/-3.5% tetraploid and 0.5+/ -0.6% octaploid. However, in the adult liver, small, mononuclear cells were also present with granularity and autofluorescence comparable to fetal hepatoblasts, as well as glucose-6-phosphatase activity, diploi d DNA in 89.0%+/-2.1% of the nuclei, and with increased granularity in culture. Since general features of terminal cellular differentiation and senescence include cessation of mitotic activity, polyploidy and a ccumulation of autofluorescent secondary lysosomes, our data suggest t hat liver cells too undergo a process of terminal differentiation.