Differentiation-specific regulation of transgene expression in a diploid epithelial, cell line derived from the normal F344 rat liver

To establish the differentiation potential of progenitor cells, non-parench ymal epithelial cells from the F344 rat liver (FNRL cells) were studied. Th ese cells reacted with the OV-6 antibody marker of oval cells, but were neg ative for hepatocyte markers (albumin, transferrin, glycogen, glucose-6-pho sphatase, H4 antigen), biliary markers (gamma glutamyl transpeptidase, cyto keratin-19), and alpha-fetoprotein, although exposure to sodium butyrate in duced nascent albumin and alpha-fetoprotein mRNA transcription. When stably transduced, FNRL cells expressed a retroviral promotor-driven lacZ reporte r in vitro, similar to transgene expression in hepatocyte-derived HepG2 cel ls. However, lacZ expression in FNRL cells was rapidly extinguished in inta ct animals, whereas the reporter remained active in HepG2 cells. Transplant ed FNRL cells showed copious glucose-6-phosphatase expression; however, the cell differentiation programme remained incomplete, despite two-thirds par tial hepatectomy, D-galactosamine treatment or bile duct ligation, Interest ingly, lacZ expression resumed in cultures of FNRL cells explanted from rec ipients. Moreover, lacZ expression was down-regulated by gamma-interferon i n FNRL cells, without affecting lacZ activity in HepG2 cells. The data indi cate that although subpopulations of oval cells may not fully differentiate into mature hepatocytes, these cells might serve critical functions, such as glucose utilization, and help survival after liver injury. Also, introdu ced genes may be regulated in progenitor cells at multiple levels, includin g by interactions between regulatory sequences, differentiation-specific ce llular factors, and extracellular signals; in vivo studies are thus especia lly important for analysing gene regulation in progenitor cells. Copyright (C) 1999 John Wiley & Sons, Ltd.