신동헌 (University of Pittsburgh)

한빛사논문

조회1,203

University of Pittsburgh

CV File 129 kb

Gastroenterology, Available online 26 September 2018 | https://doi.org/10.1053/j.gastro.2018.09.039 Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8

Sungjin Ko^1,2,*, Jacquelyn O. Russell², Jianmin Tian^2,3, Ce Gao⁵, Makoto Kobayashi⁶, Rilu Feng⁷, Xiaodong Yuan⁷, Chen Shao⁸, Huiguo Ding⁹, Minakshi Poddar², Sucha Singh², Joseph Locker^2,3, Hong-Lei Weng⁷, Satdarshan P. Monga^2,3,4, and Donghun Shin^1,3,*¹Department of Developmental Biology, McGowan Institute for Regenerative Medicine,

²Department of Pathology, ³Pittsburgh Liver Research Center, and ⁴Department of Medicine, University of Pittsburgh, Pittsburgh, USA

⁵MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China

⁶Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

⁷Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

⁸Department of Pathology and 9Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Capital Medical University, Beijing, China

^*Correspondence

Abstract

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 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 PCR. We studied mice in which hepatocyte-specific deletion of β-catenin (Ctnnb1^flox/flox mice injected with AAV8-TBG-Cre) induces differentiation of LPCs into hepatocytes following 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 β-catenin impaired differentiation of LPCs into hepatocytes following 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 following the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.

Key words: hepatic, development, CDE diet, signal transduction

논문정보

형식Research article
게재일2018년 09월 (BRIC 등록일 2018-10-04)
연구진국외 연구진
분야 의약학 > 응용의학

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