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Updated: May 14, 2025
Seven Steps to Stellate Cells
Published on: May 10, 2011
Hepatic stellate cell-derived microfibrillar-associated protein 2 prevents liver fibrosis by regulating extracellular
Wen Zhang1,2,3, Wenyue Wu1,2,3, Ning Zhang1,2,3
1Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Abstract:
Microfibrillar-associated protein 2 (MFAP-2) is a crucial component of the extracellular matrix (ECM) microfibrils, yet its role in liver fibrosis remains elusive. Methods: Human tissue arrays and mouse models of fibrosis progression and resolution were used to investigate MFAP-2 expression patterns. Mfap2 deficiency (Mfap2 -/-) or overexpression (ovMfap2) mice were subjected to carbon tetrachloride (CCl4) injection or bile duct ligation (BDL) to induce liver fibrosis. Histological, biochemical, bulk, or single-cell RNA-sequencing (scRNA-seq), proteomics to analyze the matrisome, and in vitro studies were conducted. Results: MFAP-2 was predominantly enriched in activated hepatic stellate cells (HSCs) and upregulated in advanced liver fibrosis. Although Mfap2 ablation had minimal impact on collagen deposition during CCl4 injection, it significantly delayed fibrosis regression after CCl4 cessation. The delayed fibrosis regression due to Mfap2 deficiency was likely linked to aggravated intrahepatic inflammation, ECM stabilization, and activated focal adhesion signaling in HSCs. Mechanically, inhibiting HSC-derived Mfap2 enhanced HSC interactions and increased matrisome protein production, while reducing the interaction between HSCs and liver-resident macrophages by decreasing macrophage migration inhibitory factor secretion from HSCs. Additionally, we validated the role of Mfap2 deletion in liver fibrosis using the BDL mouse model, demonstrating a more pronounced effect on fibrosis progression. Adeno-associated virus vector (serotype 6)-mediated Mfap2 overexpression in HSCs conferred protection against liver fibrosis in both models. Conclusion: This study reveals the compensatory protective effects of HSC-derived MFAP-2 on liver fibrosis and its underlying mechanisms. Enhancing MFAP-2 in HSCs may therefore benefit patients with liver fibrosis.
Insights
Microfibrillar-associated protein 2 (MFAP-2) protects against liver fibrosis by supporting extracellular matrix resolution and reducing inflammation. Enhancing MFAP-2 in hepatic stellate cells may offer a therapeutic strategy for liver fibrosis patients.
Area of Science:
- Extracellular Matrix Biology
- Liver Fibrosis Pathogenesis
- Cellular Signaling in Fibrosis
Background:
- Microfibrillar-associated protein 2 (MFAP-2) is an extracellular matrix component with an unclear role in liver fibrosis.
- Activated hepatic stellate cells (HSCs) are key drivers of liver fibrosis through extracellular matrix deposition.
Purpose of the Study:
- To investigate the role of MFAP-2 in liver fibrosis progression and resolution.
- To elucidate the mechanisms by which MFAP-2 influences hepatic stellate cell behavior and extracellular matrix dynamics.
Main Methods:
- Analysis of MFAP-2 expression in human and mouse liver fibrosis models.
- Utilized Mfap2 knockout and overexpression mouse models subjected to carbon tetrachloride (CCl4) or bile duct ligation (BDL) induced fibrosis.
- Employed histological, biochemical, RNA-sequencing, proteomics, and in vitro assays to assess fibrosis, inflammation, and cellular interactions.
Main Results:
- MFAP-2 is upregulated in activated HSCs and advanced liver fibrosis.
- Mfap2 deficiency delayed fibrosis regression, associated with increased inflammation, ECM stabilization, and altered HSC signaling.
- MFAP-2 overexpression in HSCs demonstrated a protective effect against liver fibrosis in both CCl4 and BDL models.
Conclusions:
- HSC-derived MFAP-2 exerts compensatory protective effects in liver fibrosis.
- MFAP-2 influences HSC-macrophage interactions and matrisome production.
- Therapeutic strategies targeting MFAP-2 in HSCs hold potential for treating liver fibrosis.
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