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Cited by 30Liver physiology and pathologyLiver Disease Diagnosis and TreatmentLiver Diseases and Immunity

Matrisome gene-based subclassification of patients with liver fibrosis identifies clinical and molecular heterogeneities

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Chen, Wei, Sun, Yameng, Chen, Shuyan, Ge, Xiaodong, Zhang, Wen, Zhang, Ning, Wu, Xiaoning, Song, Zhuolun +8 more·2023·Hepatology
DOI 10.1097/hep.0000000000000423PMC PMC10524702
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Abstract

Background & Aims: Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology. Our aim was to unveil matrisome genes not dependent on etiology, which are clinically relevant to liver fibrosis. Approach & Results: We used transcriptomic profiles from liver fibrosis cases of different etiologies to identify and validate liver fibrosis-specific matrisome genes (LFMGs) and their clinical and biological relevance. Dysregulation patterns and cellular landscapes of LFMGs were further explored in mouse models of liver fibrosis progression and regression by bulk and single-cell RNA sequencing. We identified 35 LFMGs, independent of etiology, representing an LFMG signature defining liver fibrosis. Expression of the LFMG signature depended on histological severity and was reduced in regressive livers. Patients with liver fibrosis, even with identical pathological scores, could be subclassified into LFMG Low and LFMG High, with distinguishable clinical, cellular, and molecular features. Single-cell RNA sequencing revealed that microfibrillar-associated protein 4+ activated HSC increased in LFMG High patients and were primarily responsible for the LFMG signature expression and dysregulation. Conclusions: The microfibrillar-associated protein 4+ -activated HSC-derived LFMG signature classifies patients with liver fibrosis with distinct clinical and biological characteristics. Our findings unveil hidden information from liver biopsies undetectable using traditional histologic assessments.

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  • Macrophages can respond to matrix mechanical changes to activate HSCs, thereby promoting the development of liver fibrosis.

    “Although the literature indicated that the macrophages can respond to matrix mechanical changes to activate HSCs, thereby promoting the development of liver fibrosis (43)”

    From Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation (2025) · cites this paper as [43]

    The Introduction (page unavailable) says that stiff extracellular matrix transmits mechanical forces that recruit and activate profibrogenic cells. The Results (page unavailable) identify activated HSCs as a major cellular source of the fibrosis-associated signature, but neither passage says macrophages sense matrix changes and then activate HSCs. That macrophage-mediated step is unsupported. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Chen, W., Sun, Y., Chen, S., Ge, X., Zhang, W., Zhang, N., Wu, X., Song, Z., Han, H., Desert, R., Yan, X., Yang, A., Das, S., Athavale, D., Nieto, N., & You, H.
Affiliations
  • Capital Medical University (CN)
  • University of Illinois Chicago (US)
  • Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
Corresponding author
  • Nieto, Natalia
  • You, Hong
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-04-27
Volume
78
Issue
4
Pages
1118-1132
ISSN
0270-9139 (ISSN-L)
DOI
10.1097/hep.0000000000000423
PMC
PMC10524702
OpenAlex
W4367047840
Cited by
30
References
3
Citations by year
2026: 9 · 2025: 18 · 2024: 3
FWCI
5.07
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01BX005093)
  • National Science and Technology Major Project
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK111677, R01DK134461)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
liver fibrosis, extracellular matrix, microfibrillar-associated protein 4, activated hepatic stellate cells, fibrosis regression, histological severity, single-cell RNA sequencing, gene expression signatures
MeSH terms
Animals, Disease Models, Animal, Extracellular Matrix, Humans, Liver, Liver Cirrhosis, Extracellular Matrix Proteins, Mice, Hepatic Stellate Cells

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