WHOLESALE HEPATOCYTIC DIFFERENTIATION IN THE RAT FROM DUCTULAR OVAL CELLS, THE PROGENY OF BILIARY STEM-CELLS

Background/Aims: Biliary epithelial cells (ductular oval cells) migrat e into the periportal and midzonal parenchyma when hepatocyte regenera tion after injury is significantly impeded, The potential of oval cell s to differentiate into hepatocytes has been questioned. We have sough t to resolve this issue using the modified Solt-Farber procedure in wh ich 2-acetylaminofluorene is used to block hepatocyte regeneration in partially hepatectomized rats. Methods: Rats received 2-acetylaminoflu orene by oral gavage for 6 days before and up to 7 days after a two-th irds hepatectomy. The cellular reaction was visualized by the immunohi stochemical localization of intermediate filaments cytokeratins 8 and 19 and vimentin, cytochrome P450 enzymatic proteins and alpha-foetopro tein. Expression of albumin and alpha-foetoprotein mRNA transcripts we re observed in situ using antisense riboprobes. Results: During the fi rst 9 days after partial hepatectomy long strings of ductular cells sp read outwards from the portal areas. These cells exhibited strong diff use cytoplasmic staining with the anticytokeratin 8 and 19 antibodies, like authentic bile ducts, but in addition also expressed vimentin an d alpha-foetoprotein (protein and mRNA) - collectively termed the ''ov al cell phenotype''. Thereafter, these ducts rapidly vanished to be re placed by basophilic hepatocytes which lacked the oval cell phenotype, but which acquired strong expression of albumin mRNA. At 14 days afte r partial hepatectomy the oval cell phenotype was restricted to the pe ripheral margins of the newborn periportal hepatocytes, the distal tip s of the oval cell ducts, and these too had disappeared within another 7 days. Conclusions: Ductular oval cells will differentiate into hepa tocytes under appropriate experimental conditions.