PMID- 28935574 OWN - NLM STAT- MEDLINE DCOM- 20171129 LR - 20171129 IS - 1525-2191 (Electronic) IS - 0002-9440 (Linking) VI - 187 IP - 12 DP - 2017 Dec TI - Taurocholate Induces Biliary Differentiation of Liver Progenitor Cells Causing Hepatic Stellate Cell Chemotaxis in the Ductular Reaction: Role in Pediatric Cystic Fibrosis Liver Disease. PG - 2744-2757 LID - S0002-9440(17)30375-9 [pii] LID - 10.1016/j.ajpath.2017.08.024 [doi] AB - Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis; however, its cause(s) and early pathogenesis are unclear. We hypothesized that a bile acid-induced ductular reaction (DR) drives fibrogenesis. The DR was evaluated by cytokeratin-7 immunohistochemistry in liver biopsies, staged for fibrosis, from 60 children with CFLD, and it demonstrated that the DR was significantly correlated with hepatic fibrosis stage and biliary taurocholate levels. To examine the mechanisms involved in DR induction, liver progenitor cells (LPCs) were treated with taurocholate, and key events in DR evolution were assessed: LPC proliferation, LPC biliary differentiation, and hepatic stellate cell (HSC) chemotaxis. Taurocholate induced a time-dependent increase in LPC proliferation and expression of genes associated with cholangiocyte differentiation (cytokeratin 19, connexin 43, integrin beta4, and gamma-glutamyltranspeptidase), whereas the hepatocyte specification marker HNF4alpha was suppressed. Functional cholangiocyte differentiation was demonstrated via increased acetylated alpha-tubulin and SOX9 proteins, the number of primary cilia(+) LPCs, and increased active gamma-glutamyltranspeptidase enzyme secretion. Taurocholate induced LPCs to release MCP-1, MIP1alpha, and RANTES into conditioned medium causing HSC chemotaxis, which was inhibited by anti-MIP1alpha. Immunofluorescence confirmed chemokine expression localized to CK7(+) DR and LPCs in CFLD liver biopsies. This study suggests that taurocholate is involved in initiating functional LPC biliary differentiation and the development of the DR, with subsequent induction of chemokines that drive HSC recruitment in CFLD. CI - Copyright (c) 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Pozniak, Katarzyna N AU - Pozniak KN AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. FAU - Pearen, Michael A AU - Pearen MA AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. FAU - Pereira, Tamara N AU - Pereira TN AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. FAU - Kramer, Cynthia S M AU - Kramer CSM AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. FAU - Kalita-De Croft, Priyakshi AU - Kalita-De Croft P AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. FAU - Nawaratna, Sujeevi K AU - Nawaratna SK AD - Molecular Parasitology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. FAU - Fernandez-Rojo, Manuel A AU - Fernandez-Rojo MA AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. FAU - Gobert, Geoffrey N AU - Gobert GN AD - Molecular Parasitology Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Biological Sciences, Queen's University Belfast, Belfast, United Kingdom. FAU - Tirnitz-Parker, Janina E E AU - Tirnitz-Parker JEE AD - School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Bentley, Western Australia, Australia; School of Medicine and Pharmacology, University of Western Australia, Fremantle, Western Australia, Australia. FAU - Olynyk, John K AU - Olynyk JK AD - School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Bentley, Western Australia, Australia; Department of Gastroenterology & Hepatology, Fiona Stanley and Fremantle Hospitals, Perth, Western Australia, Australia; Faculty of Health Sciences, Edith Cowan University, Perth, Western Australia, Australia. FAU - Shepherd, Ross W AU - Shepherd RW AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. FAU - Lewindon, Peter J AU - Lewindon PJ AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Gastroenterology, The University of Queensland, Brisbane, Queensland, Australia. FAU - Ramm, Grant A AU - Ramm GA AD - Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: grant.ramm@qimrberghofer.edu.au. LA - eng PT - Journal Article DEP - 20170919 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 5E090O0G3Z (Taurocholic Acid) SB - IM MH - Animals MH - Cell Differentiation/drug effects MH - Cell Line MH - Chemotaxis/drug effects MH - Child MH - Cystic Fibrosis/*complications MH - Female MH - Hepatic Stellate Cells/drug effects/*pathology MH - Humans MH - Liver Cirrhosis, Biliary/etiology/*pathology MH - Male MH - Mice MH - Stem Cells/drug effects/*pathology MH - Taurocholic Acid/*metabolism/toxicity EDAT- 2017/09/25 06:00 MHDA- 2017/12/01 06:00 CRDT- 2017/09/23 06:00 PHST- 2017/04/06 00:00 [received] PHST- 2017/07/14 00:00 [revised] PHST- 2017/08/11 00:00 [accepted] PHST- 2017/09/25 06:00 [pubmed] PHST- 2017/12/01 06:00 [medline] PHST- 2017/09/23 06:00 [entrez] AID - S0002-9440(17)30375-9 [pii] AID - 10.1016/j.ajpath.2017.08.024 [doi] PST - ppublish SO - Am J Pathol. 2017 Dec;187(12):2744-2757. doi: 10.1016/j.ajpath.2017.08.024. Epub 2017 Sep 19.