在NASH中,常驻CD24 +LCN2 + LPCs通过募集TPPP3 +COL10A1 +巨噬细胞加重纤维化和炎症进展。

IF 3.3 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Min Ding, Xiaoshu Qi, Weijian Huang, Yan Lin, Hexin Yan
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引用次数: 0

摘要

据报道,常住CD24 +LCN2 +肝祖细胞(LPCs)参与了与慢性肝损伤相关的扩张导管反应和巨噬细胞介导的炎症。在各种小鼠肝脏疾病中,导管反应和巨噬细胞驱动的炎症都与肝纤维化和损伤有关。本研究旨在探讨非酒精性脂肪性肝炎(NASH)患者LPCs的分子表型及其调控机制。单细胞RNA测序(scRNA-seq)数据集用于表征临床NASH样本中LPCs的状态和分子表型。为了阐明LPCs的调控机制,我们使用CellChat和NicheNet来评估LPCs与其他细胞类型之间的细胞间通讯。研究结果通过与NASH进展、NASH小鼠模型(CDAHFD和HFD)和人类NASH肝脏样本相关的RNA测序数据集得到验证。结果表明,在NASH患者中鉴定出CD24 +LCN2 + LPCs,并发现其显著富集。细胞通讯分析预测LPCs和促炎巨噬细胞亚型之间的强相互作用。此外,在NASH中,肝脏招募外周血单核细胞(PBMC)来源的巨噬细胞并将其极化为促炎亚型。巨噬细胞亚型MP-2被确定为lpc来源信号的主要受体,表现出NF-κB通路的显著过度激活,并与肝纤维化密切相关。最后,对MP-2标记物COL10A1和TPPP3进行了表征和验证。总之,本研究揭示了常驻CD24 +LCN2 + LPCs在NASH中被激活,并通过促进促炎COL10A1 +TPPP3 +巨噬细胞亚型的激活来促进纤维化进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Resident CD24 +LCN2 + LPCs aggravate fibrosis and inflammatory progression via the recruitment of TPPP3 +COL10A1 + macrophages in NASH.

Resident CD24 +LCN2 + liver progenitor cells (LPCs) reportedly contribute to the expanding ductular reaction and macrophage-mediated inflammation associated with chronic liver damage. Both ductular reactions and macrophage-driven inflammation are associated with liver fibrosis and injury in various mouse liver disorders. This study aims to investigate the molecular phenotypes of LPCs and their regulatory mechanisms in humans with non-alcoholic steatohepatitis (NASH). Single-cell RNA sequencing (scRNA-seq) datasets are used to characterize the status and molecular phenotypes of LPCs in clinical NASH samples. To elucidate the regulatory mechanisms of LPCs, CellChat and NicheNet are employed to assess cell-cell communication between LPCs and other cell types. The findings are validated using RNA sequencing datasets associated with NASH progression, NASH mouse models (CDAHFD and HFD), and human NASH liver samples. Results show that resident CD24 +LCN2 + LPCs are identified and found to be significantly enriched in NASH patients. Cell communication analyses predict strong interactions between LPCs and proinflammatory macrophage subtypes. Additionally, in NASH, the liver recruits peripheral blood mononuclear cell (PBMC)-derived macrophages and polarizes them into proinflammatory subtypes. The macrophage subtype MP-2 is identified as the primary recipient of LPC-derived signals, exhibiting marked hyperactivation of the NF-κB pathway and a strong association with liver fibrosis. Finally, the MP-2 markers COL10A1 and TPPP3 are characterized and validated. In summary, this study reveals that resident CD24 +LCN2 + LPCs are activated in NASH and contribute to fibrosis progression by promoting the activation of the proinflammatory COL10A1 +TPPP3 + macrophage subtype.

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来源期刊
Acta biochimica et biophysica Sinica
Acta biochimica et biophysica Sinica 生物-生化与分子生物学
CiteScore
5.00
自引率
5.40%
发文量
170
审稿时长
3 months
期刊介绍: Acta Biochimica et Biophysica Sinica (ABBS) is an internationally peer-reviewed journal sponsored by the Shanghai Institute of Biochemistry and Cell Biology (CAS). ABBS aims to publish original research articles and review articles in diverse fields of biochemical research including Protein Science, Nucleic Acids, Molecular Biology, Cell Biology, Biophysics, Immunology, and Signal Transduction, etc.
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