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Relationship: 2892
Title
Activation, Stellate cells leads to Increased extracellular matrix deposition
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
AhR activation leading to liver fibrosis | adjacent | High | High | Xavier COUMOUL (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Upon activation, hepatic stellate cells undergo a transition into a myofibroblast-like phenotype, leading to excessive extracellular matrix deposition, primarily consisting of collagen type I and III, fibronectin, and other fibrillar proteins (PMID: 37152902). This activation is triggered by oxidative stress, pro-inflammatory cytokines (e.g., TGF-β, PDGF), and chronic tissue injury. Activated stellate cells express α-SMA (alpha-smooth muscle actin) and exhibit increased secretion of ECM components. This process is central to the development of fibrosis in the liver, pancreas, and retina, contributing to tissue stiffness and organ dysfunction.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
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- The relationship between stellate cell activation and ECM accumulation is well-established. TGF-β1 is a key cytokine that directly stimulates the expression of ECM-related genes (PMID: 24265236).
- Inhibition of TGF-β1 has been shown to prevent stellate cell activation and reduce collagen production (PMID: 37923895).
- Transcriptomic analyses reveal a strong correlation between stellate cell activation markers (ACTA2, COL1A1, TIMP-1) and ECM deposition in fibrotic tissues (PMID: 39062514).
Empirical Evidence
- In vitro studies: When cultured with TGF-β, stellate cells exhibit increased collagen and fibronectin production (PMID: 30584275).
- Animal models: In TGF-β or α-SMA knockout mice, chemically induced liver fibrosis (e.g., CCl₄ exposure) is significantly attenuated, indicating a direct causal role (PMID: 30584275).
- Clinical data: In patients with liver fibrosis, activated stellate cells (α-SMA+, Desmin+) are strongly correlated with the degree of ECM deposition (PMID: 38056058).
Uncertainties and Inconsistencies
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- Suppressing stellate cell activation may not completely prevent ECM deposition; other cell types (e.g., portal fibroblasts, macrophages) may also contribute.
- Species-specific differences in the regulation of stellate cell activation and ECM production may affect the translatability of animal model findings to humans.
- Certain pro-inflammatory cytokines (IL-6, TNF-α) may have context-dependent effects that modulate stellate cell activation and fibrogenesis differently.
Known modulating factors
Quantitative Understanding of the Linkage
- The relationship between stellate cell activation and ECM deposition has been quantified: for example, an increase in α-SMA over time was observed in all patients with fibrosis, indicating a correlation between fibrosis progression and α-SMA upregulation. Moreover, elevated α-SMA expression was already present at the pre-fibrotic stage in all affected patients (PMID: 24966580).
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- This KER is most relevant to hepatic tissues, where stellate cells play a crucial role in fibrosis development.
- It applies primarily to chronic fibrotic diseases such as liver fibrosis, but also potentially to chronic pancreatitis, and retinal fibrosis.
- This relationship has been observed across multiple mammalian species, although species-specific differences in regulatory pathways may influence the quantitative aspects of the response.
References
Zhao YQ, Deng XW, Xu GQ, Lin J, Lu HZ, Chen J. Mechanical homeostasis imbalance in hepatic stellate cells activation and hepatic fibrosis. Front Mol Biosci. 2023 Apr 20;10:1183808. doi: 10.3389/fmolb.2023.1183808. PMID: 37152902; PMCID: PMC10157180.
Kasahara N, Imi Y, Amano R, Shinohara M, Okada K, Hosokawa Y, Imamori M, Tomimoto C, Kunisawa J, Kishino S, Ogawa J, Ogawa W, Hosooka T. A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-β signaling in hepatic stellate cells. Sci Rep. 2023 Nov 3;13(1):18983. doi: 10.1038/s41598-023-46404-5. PMID: 37923895; PMCID: PMC10624680.
Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol. 2013 Oct;3(4):1473-92. doi: 10.1002/cphy.c120035. PMID: 24265236.
Buakaew W, Krobthong S, Yingchutrakul Y, Potup P, Thongsri Y, Daowtak K, Ferrante A, Usuwanthim K. Investigating the Antifibrotic Effects of β-Citronellol on a TGF-β1-Stimulated LX-2 Hepatic Stellate Cell Model. Biomolecules. 2024 Jul 5;14(7):800. doi: 10.3390/biom14070800. PMID: 39062514; PMCID: PMC11274813.
Mu M, Zuo S, Wu RM, Deng KS, Lu S, Zhu JJ, Zou GL, Yang J, Cheng ML, Zhao XK. Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway. Drug Des Devel Ther. 2018 Dec 3;12:4107-4115. doi: 10.2147/DDDT.S186726. Erratum in: Drug Des Devel Ther. 2019 May 24;13:1819. doi: 10.2147/DDDT.S215949. PMID: 30584275; PMCID: PMC6284527.
Parola M, Pinzani M. Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies. Mol Aspects Med. 2024 Feb;95:101231. doi: 10.1016/j.mam.2023.101231. Epub 2023 Dec 5. PMID: 38056058.
Hirabaru M, Mochizuki K, Takatsuki M, Soyama A, Kosaka T, Kuroki T, Shimokawa I, Eguchi S. Expression of alpha smooth muscle actin in living donor liver transplant recipients. World J Gastroenterol. 2014 Jun 14;20(22):7067-74. doi: 10.3748/wjg.v20.i22.7067. PMID: 24966580; PMCID: PMC4051953.