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Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages.
Tian, Siyuan; Zhou, Xia; Zhang, Miao; Cui, Lina; Li, Bo; Liu, Yansheng; Su, Rui; Sun, Keshuai; Hu, Yinan; Yang, Fangfang; Xuan, Guoyun; Ma, Shuoyi; Zheng, Xiaohong; Zhou, Xinmin; Guo, Changcun; Shang, Yulong; Wang, Jingbo; Han, Ying.
Afiliação
  • Tian S; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Zhou X; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Zhang M; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Cui L; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Li B; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Liu Y; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Su R; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Sun K; Department of Gastroenterology, The Air Force Hospital From Eastern Theater of PLA, Nanjing, 210002, Jiangsu, China.
  • Hu Y; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Yang F; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Xuan G; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Ma S; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Zheng X; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Zhou X; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Guo C; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • Shang Y; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. shangyul870222@163.com.
  • Wang J; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. jbwang002@163.com.
  • Han Y; State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China. hanying1@fmmu.edu.cn.
Stem Cell Res Ther ; 13(1): 330, 2022 07 20.
Article em En | MEDLINE | ID: mdl-35858897
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: MicroRNAs / Exossomos / Células-Tronco Mesenquimais Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2022 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: MicroRNAs / Exossomos / Células-Tronco Mesenquimais Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2022 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido