PMID- 30267710 OWN - NLM STAT- MEDLINE DCOM- 20190128 LR - 20200309 IS - 1528-0012 (Electronic) IS - 0016-5085 (Print) IS - 0016-5085 (Linking) VI - 156 IP - 1 DP - 2019 Jan TI - Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8. PG - 187-202.e14 LID - S0016-5085(18)35033-9 [pii] LID - 10.1053/j.gastro.2018.09.039 [doi] AB - BACKGROUND & AIMS: Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about the mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. METHODS: We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription polymerase chain reaction. We studied mice in which hepatocyte-specific deletion of beta-catenin (Ctnnb1(flox/flox) mice injected with Adeno-associated virus serotype 8 [AAV8]-TBG-Cre) induces differentiation of LPCs into hepatocytes after a choline-deficient, ethionine-supplemented (CDE) diet. Liver tissues were collected and analyzed by immunohistochemistry and immunoblots. We performed immunohistochemical analyses of liver tissues from patients with compensated or decompensated cirrhosis or acute on chronic liver failure (n = 15). RESULTS: Loss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of beta-catenin impaired differentiation of LPCs into hepatocytes after the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis. CONCLUSIONS: Hdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury after the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases. CI - Copyright (c) 2019 AGA Institute. Published by Elsevier Inc. All rights reserved. FAU - Ko, Sungjin AU - Ko S AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania; Department of Pathology, Pittsburgh, Pennsylvania. Electronic address: sungjin@pitt.edu. FAU - Russell, Jacquelyn O AU - Russell JO AD - Department of Pathology, Pittsburgh, Pennsylvania. FAU - Tian, Jianmin AU - Tian J AD - Department of Pathology, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania. FAU - Gao, Ce AU - Gao C AD - Ministry of Education Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China. FAU - Kobayashi, Makoto AU - Kobayashi M AD - Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. FAU - Feng, Rilu AU - Feng R AD - Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Yuan, Xiaodong AU - Yuan X AD - Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Shao, Chen AU - Shao C AD - Department of Pathology, Beijing You'an Hospital, Capital Medical University, Beijing, China. FAU - Ding, Huiguo AU - Ding H AD - Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China. FAU - Poddar, Minakshi AU - Poddar M AD - Department of Pathology, Pittsburgh, Pennsylvania. FAU - Singh, Sucha AU - Singh S AD - Department of Pathology, Pittsburgh, Pennsylvania. FAU - Locker, Joseph AU - Locker J AD - Department of Pathology, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania. FAU - Weng, Hong-Lei AU - Weng HL AD - Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Monga, Satdarshan P AU - Monga SP AD - Department of Pathology, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. FAU - Shin, Donghun AU - Shin D AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania. Electronic address: donghuns@pitt.edu. LA - eng GR - R01 DK101426/DK/NIDDK NIH HHS/United States GR - T32 EB001026/EB/NIBIB NIH HHS/United States GR - R01 CA104292/CA/NCI NIH HHS/United States GR - R01 DK062277/DK/NIDDK NIH HHS/United States GR - R01 CA204586/CA/NCI NIH HHS/United States GR - F31 DK115017/DK/NIDDK NIH HHS/United States GR - R01 DK100287/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180926 PL - United States TA - Gastroenterology JT - Gastroenterology JID - 0374630 RN - 0 (CTNNB1 protein, mouse) RN - 0 (F-Box-WD Repeat-Containing Protein 7) RN - 0 (Fbxw7 protein, zebrafish) RN - 0 (Notch3 protein, zebrafish) RN - 0 (Receptor, Notch3) RN - 0 (SOX9 Transcription Factor) RN - 0 (Sox9b protein, zebrafish) RN - 0 (Zebrafish Proteins) RN - 0 (beta Catenin) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 8) RN - EC 2.7.11.22 (cdk8 protein, zebrafish) RN - EC 3.5.1.98 (HDAC1 protein, human) RN - EC 3.5.1.98 (HDAC1 protein, zebrafish) RN - EC 3.5.1.98 (Histone Deacetylase 1) SB - IM MH - Acute-On-Chronic Liver Failure/enzymology/pathology MH - Animals MH - Bile Ducts/*enzymology/pathology MH - *Cell Differentiation MH - *Cell Proliferation MH - Choline Deficiency/genetics/metabolism/pathology MH - Cyclin-Dependent Kinase 8/genetics/*metabolism MH - Disease Models, Animal MH - F-Box-WD Repeat-Containing Protein 7/genetics/metabolism MH - Gene Expression Regulation, Developmental MH - Gene Expression Regulation, Enzymologic MH - Hepatocytes/*enzymology/pathology MH - Histone Deacetylase 1/genetics/*metabolism MH - Humans MH - Liver/*enzymology/pathology MH - Liver Cirrhosis/enzymology/pathology MH - *Liver Regeneration MH - Mice, Knockout MH - Mutation MH - Receptor, Notch3/genetics/metabolism MH - SOX9 Transcription Factor/genetics/*metabolism MH - Signal Transduction MH - Stem Cells/*enzymology/pathology MH - Zebrafish/genetics/metabolism MH - Zebrafish Proteins/genetics/*metabolism MH - beta Catenin/genetics/metabolism PMC - PMC6309465 MID - NIHMS1508166 OTO - NOTNLM OT - CDE Diet OT - Development OT - Hepatic OT - Signal Transduction COIS- Disclosures: The authors declare no conflict of interest. EDAT- 2018/09/30 06:00 MHDA- 2019/01/29 06:00 PMCR- 2020/01/01 CRDT- 2018/09/30 06:00 PHST- 2017/03/02 00:00 [received] PHST- 2018/09/17 00:00 [revised] PHST- 2018/09/18 00:00 [accepted] PHST- 2018/09/30 06:00 [pubmed] PHST- 2019/01/29 06:00 [medline] PHST- 2018/09/30 06:00 [entrez] PHST- 2020/01/01 00:00 [pmc-release] AID - S0016-5085(18)35033-9 [pii] AID - 10.1053/j.gastro.2018.09.039 [doi] PST - ppublish SO - Gastroenterology. 2019 Jan;156(1):187-202.e14. doi: 10.1053/j.gastro.2018.09.039. Epub 2018 Sep 26.