Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles
Abstract Background Activated 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...
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BMC
2025-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Online Access: | https://doi.org/10.1186/s13046-025-03380-0 |
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| author | Yufeng Sun Min Zhao Li Cheng Xiaoqian He Shiqi Shen Jiaying Lv Junyu Zhang Qian Shao Wenxuan Yin Fengbo Zhao Rui Sun Peng Lu Yuhua Ji Xin Wei Wang Juling Ji |
| author_facet | Yufeng Sun Min Zhao Li Cheng Xiaoqian He Shiqi Shen Jiaying Lv Junyu Zhang Qian Shao Wenxuan Yin Fengbo Zhao Rui Sun Peng Lu Yuhua Ji Xin Wei Wang Juling Ji |
| author_sort | Yufeng Sun |
| collection | DOAJ |
| description | Abstract Background Activated 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. Methods The 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. Results We 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. Conclusion Collectively, 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. |
| format | Article |
| id | doaj-art-25ce63e0d8d546768df3ac58b232f84d |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-25ce63e0d8d546768df3ac58b232f84d2025-08-20T02:11:43ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-04-0144112510.1186/s13046-025-03380-0Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesiclesYufeng Sun0Min Zhao1Li Cheng2Xiaoqian He3Shiqi Shen4Jiaying Lv5Junyu Zhang6Qian Shao7Wenxuan Yin8Fengbo Zhao9Rui Sun10Peng Lu11Yuhua Ji12Xin Wei Wang13Juling Ji14Department of Pathology, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityBasic Medical Research Center, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityDepartment of Pathology, Medical School of Nantong UniversityKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong UniversityLaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer InstituteDepartment of Pathology, Medical School of Nantong UniversityAbstract Background Activated 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. Methods The 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. Results We 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. Conclusion Collectively, 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.https://doi.org/10.1186/s13046-025-03380-0 |
| spellingShingle | Yufeng Sun Min Zhao Li Cheng Xiaoqian He Shiqi Shen Jiaying Lv Junyu Zhang Qian Shao Wenxuan Yin Fengbo Zhao Rui Sun Peng Lu Yuhua Ji Xin Wei Wang Juling Ji Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles Journal of Experimental & Clinical Cancer Research |
| title | Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles |
| title_full | Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles |
| title_fullStr | Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles |
| title_full_unstemmed | Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles |
| title_short | Reduction of alternative polarization of macrophages by short-term activated hepatic stellate cell-derived small extracellular vesicles |
| title_sort | reduction of alternative polarization of macrophages by short term activated hepatic stellate cell derived small extracellular vesicles |
| url | https://doi.org/10.1186/s13046-025-03380-0 |
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