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Hepatocyte to biliary epithelium transdifferentiation following methylene dianiline‐induced biliary epithelium injury
Author(s) -
Limaye Pallavi B.,
Bowen William C.,
Michalopoulos George K.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1136
Subject(s) - transdifferentiation , hepatocyte , medicine , biliary tract , biology , endocrinology , pathology , stem cell , microbiology and biotechnology , biochemistry , in vitro
We have previously demonstrated that bile duct ligation followed by biliary epithelium (BE) toxicant methylene dianiline (DAPM) treatment induces hepatocyte transdifferentiation into biliary cells. The aim of the present study was to further characterize hepatocyte transdifferentiation to BE following acute and chronic DAPM treatment. BE injury was induced by administration of a single dose of DAPM to male F344 rats. BE injury was evident within 12 h post‐DAPM administration with BE inflammation, portal triad edema, and increase in serum bilirubin and γGGTP levels. BE injury decreased by day 3 due to increased BE cell proliferation, which sustained till day 7 post DAPM administration measured by PCNA analysis. Contribution of hepatocyte to BE repair by transdifferentiation was evident by expression of BE markers, AE1/AE3 and CK19 on periportal hepatocytes. To obtain a direct evidence of hepatocyte transdifferentiation into BE, dipetidyl dipeptidase (DPPIV) chimeric rats carrying DDPIV hepatocytes were utilized. While a single dose of DAPM failed to induce hepatocyte transdifferentiation, chronic treatment of DAPM (50 mg/kg every 2 days for 3 times) resulted in phenotypic transformation of hepatocytes to BE evident by ~10% DDPIV positive bile ducts. Hepatocyte transdifferentiation was also confirmed by albumin and CK19 colocalization noted in the selective bile ducts of these rats. These data provide a direct evidence for hepatocyte to BE transdifferentiation following impaired BE proliferation.