REDUCED GROWTH CAPACITY OF HEPATOCYTES FROM C-MYC AND C-MYC TGF-ALPHATRANSGENIC MICE IN PRIMARY CULTURE/

We have previously shown that coexpression of c-myc and TGF-alpha in t he liver results in accelerated replicative senescence and promotes tu mor development in young adult transgenic mice. Here we describe the c haracteristics of hepatocyte proliferation in primary cultures establi shed from 10-week-old control, c-mpc and c-myc/TGF-alpha transgenic mi ce. A variety of cellular and functional changes occurred in the trans genic Livers at this age including enhanced polypoidization and impair ment of hepatic functions. Control mouse hepatocytes demonstrated a hi gh level of DNA synthesis in serum-free medium with a maximum at day t hree in culture at which time 70% of the cells were in S phase. In con trast, DNA synthesis peaked one day later and was reduced by 50% in th e cultured c-myc and c-myc/TGF-alpha hepatocytes. Also, higher frequen cy of apoptosis was observed in the transgenic hepatocytes. However, i n hepatocytes isolated from c-myc/TGF-alpha mice, which show early app earance of preneoplastic lesions in vivo, the DNA synthesis continued for 6 days in culture in contrast to a sharp decrease in the labeling index of control and c-myc hepatocytes after 3-4 days in culture. The results suggest that proliferative features of the transgenic hepatocy tes in vitro reflect tile general properties of these cells in vivo an d thus may provide a model for studies on senescence and transformatio n of hepatocytes. (C) 1996 Academic Press, Inc.