Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages
Abstract Background Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study...
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-022-03010-y |
| _version_ | 1817969688550834176 |
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| author | Siyuan Tian Xia Zhou Miao Zhang Lina Cui Bo Li Yansheng Liu Rui Su Keshuai Sun Yinan Hu Fangfang Yang Guoyun Xuan Shuoyi Ma Xiaohong Zheng Xinmin Zhou Changcun Guo Yulong Shang Jingbo Wang Ying Han |
| author_facet | Siyuan Tian Xia Zhou Miao Zhang Lina Cui Bo Li Yansheng Liu Rui Su Keshuai Sun Yinan Hu Fangfang Yang Guoyun Xuan Shuoyi Ma Xiaohong Zheng Xinmin Zhou Changcun Guo Yulong Shang Jingbo Wang Ying Han |
| author_sort | Siyuan Tian |
| collection | DOAJ |
| description | Abstract Background Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs. Methods Carbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot. Results MSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis. Conclusions These findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis. |
| first_indexed | 2024-04-13T20:24:21Z |
| format | Article |
| id | doaj.art-f737994c3a15412893e39020386110de |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-04-13T20:24:21Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-f737994c3a15412893e39020386110de2022-12-22T02:31:25ZengBMCStem Cell Research & Therapy1757-65122022-07-0113112010.1186/s13287-022-03010-yMesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophagesSiyuan Tian0Xia Zhou1Miao Zhang2Lina Cui3Bo Li4Yansheng Liu5Rui Su6Keshuai Sun7Yinan Hu8Fangfang Yang9Guoyun Xuan10Shuoyi Ma11Xiaohong Zheng12Xinmin Zhou13Changcun Guo14Yulong Shang15Jingbo Wang16Ying Han17State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityDepartment of Gastroenterology, The Air Force Hospital From Eastern Theater of PLAState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical UniversityAbstract Background Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs. Methods Carbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot. Results MSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis. Conclusions These findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis.https://doi.org/10.1186/s13287-022-03010-yLiver fibrosisMesenchymal stem cellsExosomemiR-148aMacrophage polarization |
| spellingShingle | Siyuan Tian Xia Zhou Miao Zhang Lina Cui Bo Li Yansheng Liu Rui Su Keshuai Sun Yinan Hu Fangfang Yang Guoyun Xuan Shuoyi Ma Xiaohong Zheng Xinmin Zhou Changcun Guo Yulong Shang Jingbo Wang Ying Han Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages Stem Cell Research & Therapy Liver fibrosis Mesenchymal stem cells Exosome miR-148a Macrophage polarization |
| title | Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages |
| title_full | Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages |
| title_fullStr | Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages |
| title_full_unstemmed | Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages |
| title_short | Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages |
| title_sort | mesenchymal stem cell derived exosomes protect against liver fibrosis via delivering mir 148a to target klf6 stat3 pathway in macrophages |
| topic | Liver fibrosis Mesenchymal stem cells Exosome miR-148a Macrophage polarization |
| url | https://doi.org/10.1186/s13287-022-03010-y |
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