Atypical cholangiocytes derived from hepatocyte-cholangiocyte transdifferentiation mediated by COX-2: a kind of misguided liver regeneration.

IF 5 3区 医学 Q2 IMMUNOLOGY Inflammation and Regeneration Pub Date : 2023-07-14 DOI:10.1186/s41232-023-00284-4
Tian Lan, Yang Tai, Chong Zhao, Yang Xiao, Zhu Yang, Linhao Zhang, Can Gan, Wenting Dai, Huan Tong, Chengwei Tang, Zhiyin Huang, Jinhang Gao
{"title":"Atypical cholangiocytes derived from hepatocyte-cholangiocyte transdifferentiation mediated by COX-2: a kind of misguided liver regeneration.","authors":"Tian Lan,&nbsp;Yang Tai,&nbsp;Chong Zhao,&nbsp;Yang Xiao,&nbsp;Zhu Yang,&nbsp;Linhao Zhang,&nbsp;Can Gan,&nbsp;Wenting Dai,&nbsp;Huan Tong,&nbsp;Chengwei Tang,&nbsp;Zhiyin Huang,&nbsp;Jinhang Gao","doi":"10.1186/s41232-023-00284-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism.</p><p><strong>Methods: </strong>A thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. The biliary tract was injected with ink and visualized by whole liver optical clearing. Serum and liver bile acid (BA) concentrations were measured. Either a COX-2 selective inhibitor or a β-catenin pathway inhibitor was administered in vitro.</p><p><strong>Results: </strong>Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-β/β-catenin signaling pathway. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-β-TGFBR1-β-catenin pathway in vitro.</p><p><strong>Conclusions: </strong>Atypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-β-TGFBR1-β-catenin pathway and improve liver function.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":"43 1","pages":"37"},"PeriodicalIF":5.0000,"publicationDate":"2023-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10347763/pdf/","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inflammation and Regeneration","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s41232-023-00284-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 1

Abstract

Background: Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism.

Methods: A thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. The biliary tract was injected with ink and visualized by whole liver optical clearing. Serum and liver bile acid (BA) concentrations were measured. Either a COX-2 selective inhibitor or a β-catenin pathway inhibitor was administered in vitro.

Results: Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-β/β-catenin signaling pathway. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-β-TGFBR1-β-catenin pathway in vitro.

Conclusions: Atypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-β-TGFBR1-β-catenin pathway and improve liver function.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
COX-2介导肝细胞-胆管细胞转分化产生的非典型胆管细胞:一种误入歧途的肝再生。
背景:肝细胞-胆管细胞转分化(HCT)是慢性损伤后肝再生中胆管细胞增殖的潜在来源。本研究旨在确定慢性肝损伤后的HCT,验证HCT对肝脏修复的影响,通过了解其机制避免有害再生。方法:建立野生型(WT-TAA组)和COX-2全敲除组(KO-TAA组)小鼠肝损伤模型。在体内和离体小鼠肝细胞中,通过肝细胞和胆管细胞标记物的染色鉴定HCT。胆道注射墨水,全肝光学清视。测定血清和肝脏胆汁酸(BA)浓度。在体外给予COX-2选择性抑制剂或β-catenin途径抑制剂。结果:慢性肝损伤时肝内小管反应与COX-2上调有关。免疫荧光和RNA测序表明,非典型胆管细胞具有介于肝细胞和胆管细胞之间的中间遗传表型,可能来源于肝细胞。HCT导致胆道系统结构受损,BA代谢失调,这是由TGF-β/β-catenin信号通路介导的。基因缺失或药物抑制COX-2可显著降低体内HCT。COX-2选择性抑制剂依托妥昔布体外通过TGF-β-TGFBR1-β-catenin途径抑制HCT。结论:非典型胆管细胞可来源于慢性肝损伤时胆汁引流系统发育不良和BA稳态失衡的HCT。抑制COX-2可通过COX-2- tgf -β-TGFBR1-β-catenin通路改善HCT,改善肝功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
期刊最新文献
Th22 is the effector cell of thymosin β15-induced hair regeneration in mice The gut-liver axis in hepatobiliary diseases Unveiling dynamic interactions: in vivo imaging chronicles inflammation and regeneration in living organisms Inter-organ communication involved in metabolic regulation at the whole-body level A disease-specific iPS cell resource for studying rare and intractable diseases.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1