title: Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury.
abstract: Whether hepatocytes can convert into biliary epithelial cells (BECs) during biliary injury is much debated. To test this concept, we traced the fate of genetically labeled [dipeptidyl peptidase IV (DPPIV)-positive] hepatocytes in hepatocyte transplantation model following acute hepato-biliary injury induced by 4,4'-methylene-dianiline (DAPM) and D-galactosamine (DAPM+D-gal) and in DPPIV-chimeric liver model subjected to acute (DAPM+D-gal) or chronic biliary injury caused by DAPM and bile duct ligation (DAPM+BDL). In both models before biliary injury, BECs are uniformly DPPIV-deficient and proliferation of DPPIV-deficient hepatocytes is restricted by retrorsine. We found that mature hepatocytes underwent a stepwise conversion into BECs after biliary injury. In the hepatocyte transplantation model, DPPIV-positive hepatocytes entrapped periportally proliferated, and formed two-layered plates along portal veins. Within the two-layered plates, the hepatocytes gradually lost their hepatocytic identity, proceeded through an intermediate state, acquired a biliary phenotype, and subsequently formed bile ducts along the hilum-to-periphery axis. In DPPIV-chimeric liver model, periportal hepatocytes expressing hepatocyte nuclear factor-1β (HNF-1β) were exclusively DPPIV-positive and were in continuity to DPPIV-positives bile ducts. Inhibition of hepatocyte proliferation by additional doses of retrorsine in DPPIV-chimeric livers prevented the appearance of DPPIV-positive BECs after biliary injury. Moreover, enriched DPPIV-positive BEC/hepatic oval cell transplantation produced DPPIV-positive BECs or bile ducts in unexpectedly low frequency and in mid-lobular regions. These results together suggest that mature hepatocytes but not contaminating BECs/hepatic oval cells are the sources of periportal DPPIV-positive BECs. We conclude that mature hepatocytes contribute to biliary regeneration in the environment of acute and chronic biliary injury through a ductal plate configuration without the need of exogenously genetic or epigenetic manipulation.
authors: Department of Pediatrics, Taipei Tzu-Chi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan; Department of Pediatrics, Buddhist Tzu-Chi University College of Medicine, Hualien, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Ya-Hui
authors: YH
authors: Chen
authors: Hepatitis Research Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Hui-Ling
authors: HL
authors: Chen
authors: Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Chin-Sung
authors: CS
authors: Chien
authors: Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Shang-Hsin
authors: SH
authors: Wu
authors: Hepatitis Research Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Yi-Tian
authors: YT
authors: Ho
authors: Department of Pediatrics, Taipei Tzu-Chi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan; Department of Pediatrics, Buddhist Tzu-Chi University College of Medicine, Hualien, Taiwan.
authors: Chun-Hsien
authors: CH
authors: Yu
authors: Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Mei-Hwei
authors: MH
authors: Chang
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001652:Bile Ducts / Q000166:cytology / Q000187:drug effects / Q000293:injuries* / Q000502:physiology*; D054338:Cell Transdifferentiation / Q000187:drug effects; D017690:Cell Transplantation; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005688:Galactosamine / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D051381:Rats; D012038:Regeneration / Q000187:drug effects; D001559:Benzhydryl Compounds
chemical_list: D000814:Aniline Compounds; D018819:Dipeptidyl Peptidase 4; D005688:Galactosamine; D011763:Pyrrolizidine Alkaloids; C009505:4,4'-diaminodiphenylmethane; D001559:Benzhydryl Compounds; C003300:retrorsine