ArticleJournal of experimental & clinical cancer research : CR2025
Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Driving tumor-associated macrophages to a CXCL9Cell reports. Medicine · 2026Article
- Modeling hepatic fibrosis in TP53 knockout iPSC-derived human liver organoids.Molecular oncology · 2026Article
- Predictive Value of Age-Adjusted Charlson Comorbidity Index on Survival Outcomes of Hepatocellular Carcinoma Patients with Comorbidities Undergoing Radiofrequency Ablation.Journal of hepatocellular carcinoma · 2026Article
- Prognostic value of M2 macrophage-related genes and their importance in the immunotherapy response in hepatocellular carcinoma.Oncology letters · 2025Article
- Novel regulators of hepatic macrophages in liver fibrosis.Frontiers in immunology · 2025Review
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Authors and funding
15 authors.
Funding
Abstract
backgroundActivated hepatic stellate cells (HSCs) induce alternative (M2) polarization of macrophages and contribute to the progression of fibrosis and hepatocellular carcinoma (HCC). However, the effects of small extracellular vesicles released by HSCs (HSC-sEVs) during activation remain largely unknown.
methodsThe aim of this study was to investigate the role of extracellular vesicles released by HSCs (HSC-sEVs) at different stages of activation in macrophage polarization. The effects of sEVs from short-term activated and long-term activated HSCs on liver macrophages was studied. Small RNA sequencing analyses were performed to obtain differential miRNAs transported by the short-term and long-term activated HSC- sEVs. The in vivo effects of short-term activated HSC-sEV-specific miRNA on liver macrophage and liver fibrosis were confirmed in a CCl4-induced liver injury mouse model. To study the tumor suppressive effects of the macrophages educated by short-term activated HSC-sEV-specific miRNA, human hepatoma cells were mixed and subcutaneously cotransplanted with miR-99a-5p mimic-pretreated macrophages.
resultsWe found that consistent with activated HSCs, long-term activated HSC-sEVs (14dHSC-sEVs) induce bone marrow-derived monocytes (MOs) toward an M2 phenotype, but short-term activated HSC-sEVs (3dHSC-sEVs) induce the resident macrophages (Kupffer cells, KCs) toward a classically activated (M1) phenotype. We identified five 3dHSC-sEV-specific miRNAs, including miR-99a-5p. In vitro and in vivo experiments support that miR-99a-5p negatively regulates alternative polarization of macrophages, decreases collagen deposition in chronic liver injury model, and suppresses the progression of hepatoma in a xenograft model partially by targeting CD93.
conclusionCollectively, our work reveals an unexpected proinflammatory role of 3dHSC-sEVs, preliminarily explores the underlying mechanism, and evaluates the therapeutic potential of 3dHSC-sEV-specific miR-99a-5p for liver fibrosis and tumorigenesis.
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