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肝细胞中的成纤维细胞生长因子受体3可保护肝脏免受毒素诱导的肝损伤和纤维化。

Fibroblast growth factor receptor 3 in hepatocytes protects from toxin-induced liver injury and fibrosis.

作者信息

Fearon Abbie E, Slabber Coenraad F, Kuklin Andrii, Bachofner Marc, Tortola Luigi, Pohlmeier Lea, Pantasis Sophia, Hornemann Thorsten, Chen Lin, Kopf Manfred, Werner Sabine

机构信息

Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.

Institute of Clinical Chemistry, University Hospital Zurich, 8092 Zurich, Switzerland.

出版信息

iScience. 2021 Sep 16;24(10):103143. doi: 10.1016/j.isci.2021.103143. eCollection 2021 Oct 22.

DOI:10.1016/j.isci.2021.103143
PMID:34646985
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8497853/
Abstract

The liver's remarkable regenerative capacity is orchestrated by several growth factors and cytokines. Fibroblast growth factor receptor 3 (Fgfr3) is frequently overexpressed in hepatocellular carcinoma and promotes cancer aggressiveness, whereas its role in liver homeostasis, repair and regeneration is unknown. We show here that Fgfr3 is expressed by hepatocytes in the healthy liver. Its major ligand, Fgf9, is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibit increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury. This was not a consequence of immunological alterations in the non-injured liver as revealed by comprehensive flow cytometry analysis. Rather, loss of Fgfr3 altered the expression of metabolic and pro-fibrotic genes in hepatocytes. These results identify a paracrine Fgf9-Fgfr3 signaling pathway that protects from toxin-induced cell death and the resulting liver fibrosis and suggests a potential use of FGFR3 ligands for therapeutic purposes.

摘要

肝脏卓越的再生能力是由多种生长因子和细胞因子共同调控的。成纤维细胞生长因子受体3（Fgfr3）在肝细胞癌中经常过度表达，并促进癌症侵袭性，而其在肝脏稳态、修复和再生中的作用尚不清楚。我们在此表明，Fgfr3在健康肝脏的肝细胞中表达。其主要配体Fgf9主要由非实质细胞表达，并在损伤后上调。肝细胞中缺乏Fgfr3的小鼠在急性毒素处理后组织坏死增加，长期损伤后纤维化更严重。综合流式细胞术分析表明，这并非未受伤肝脏免疫改变的结果。相反，Fgfr3的缺失改变了肝细胞中代谢和促纤维化基因的表达。这些结果确定了一种旁分泌Fgf9-Fgfr3信号通路，该通路可保护细胞免受毒素诱导的细胞死亡及由此导致的肝纤维化，并提示FGFR3配体在治疗方面的潜在用途。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/e3c57aaa9c17/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/c6e0eaf782c7/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/54d8c6c41535/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/0cdfe965a736/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/40a436b3990f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/bd9508dedc34/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/e3c57aaa9c17/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/c6e0eaf782c7/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/54d8c6c41535/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/0cdfe965a736/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/40a436b3990f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/bd9508dedc34/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d575/8497853/e3c57aaa9c17/gr5.jpg

相似文献

[1]
Fibroblast growth factor receptor 3 in hepatocytes protects from toxin-induced liver injury and fibrosis.

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[2]
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[3]
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[4]
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[5]
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Am J Physiol Lung Cell Mol Physiol. 2016-4-1

[6]
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[7]
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[8]
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[9]
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[10]
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[1]
Ellipticine targets FGFR3 to mediate the RAS/MAPK-P38 signalling pathway to induce apoptosis in hepatocellular carcinoma cells.

3 Biotech. 2025-5

[2]
Enhancer landscape of lung neuroendocrine tumors reveals regulatory and developmental signatures with potential theranostic implications.

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[3]
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Clin Rheumatol. 2024-10

[4]
Histopathological Spectrum and Molecular Characterization of Liver Tumors in the Setting of Fontan-Associated Liver Disease.

Cancers (Basel). 2024-1-11

[5]
Efficient and reproducible generation of human induced pluripotent stem cell-derived expandable liver organoids for disease modeling.

Sci Rep. 2023-12-22

本文引用的文献

[1]
Role of fibroblast growth factor signalling in hepatic fibrosis.

Liver Int. 2021-6

[2]
The KEAP1-NRF2 System as a Molecular Target of Cancer Treatment.

Cancers (Basel). 2020-12-26

[3]
Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis.

Sci Transl Med. 2020-9-30

[4]
Time serial transcriptome reveals as a key gene in hepatocellular carcinoma development.

Cancer Biol Med. 2020-5-15

[5]
Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds.

Nat Commun. 2020-5-25

[6]
Interaction of FGF9 with FGFR3-IIIb/IIIc, a putative driver of growth and aggressive behaviour of hepatocellular carcinoma.

Liver Int. 2020-9

[7]
Fibroblast Growth Factor 9 is expressed by activated hepatic stellate cells and promotes progression of hepatocellular carcinoma.

Sci Rep. 2020-3-11

[8]
Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase-like 4: New Evidence From Three-Dimensional Skin-like Tissues.

Arthritis Rheumatol. 2020-4-4

[9]
Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy.

Nephrology (Carlton). 2018-9

[10]
Fibroblast growth factors: key players in regeneration and tissue repair.

Development. 2017-11-15

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