维甲酸为急性肝衰竭中肝脏祖细胞的活化创造了有利的微环境。

IF 5.6 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Communications Pub Date : 2024-07-18 eCollection Date: 2024-08-01 DOI:10.1097/HC9.0000000000000483
Sai Wang, Frederik Link, Stefan Munker, Wenjing Wang, Rilu Feng, Roman Liebe, Yujia Li, Ye Yao, Hui Liu, Chen Shao, Matthias P A Ebert, Huiguo Ding, Steven Dooley, Hong-Lei Weng, Shan-Shan Wang
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引用次数: 0

摘要

背景:当急性肝衰竭(ALF)发生大面积坏死时,被称为肝祖细胞(LPC)的造血干细胞需要在一种称为导管反应的过程中快速扩增以维持生存。迄今为止,这一过程的基本机制还不完全清楚。在 ALF 中,活化的造血干细胞会分泌高水平的视黄酸(RA),视黄酸是一种在胚胎发育过程中具有多种作用的分子。我们推测RA在ALF期间的导管反应中起着关键作用:方法:我们进行了 RNAseq 研究,以确定 HepaRG LPCs 中受全反式维甲酸(atRA)处理影响的分子信号通路。在经阿特拉处理或与 LX-2 细胞共培养的 HepaRG 细胞以及 ALF 患者的肝组织中进行了功能测试:结果:在 ALF 条件下,活化的造血干细胞分泌 RA,诱导 RARα 在 LPCs 中核转位。RNAseq数据和对HepaRG细胞的研究显示,atRA治疗激活了WNT-β-Catenin通路,增强了干性基因(SOX9、AFP等),增加了能量储存,并以RARα核转位依赖的方式提高了ATP结合盒转运体的表达。此外,在 HepaRG 与 LX-2 细胞的共培养系统中证实了 atRA 治疗诱导的途径。LPCs中显示RARα核转位的ALF患者的MELD评分明显优于未显示RARα核转位的患者:结论:在 ALF 期间,活化的造血干细胞分泌的 RA 可促进 LPC 的活化,这是随后 LPC 介导的肝脏再生的先决条件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure.

Background: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF.

Methods: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF.

Results: Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-β-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without.

Conclusions: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.

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来源期刊
Hepatology Communications
Hepatology Communications GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
8.00
自引率
2.00%
发文量
248
审稿时长
8 weeks
期刊介绍: Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction. ​
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