期刊论文详细信息
Journal of Nanobiotechnology
3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway
Weili Gu1  Shuai Zhang1  Jie Cao2  Bailin Wang3  Yimeng Ou4  Keqiang Ma5  Mark A. Zern6  Tingting Guo7  Shoupei Liu7  Haibin Wu7  Yingjie Fu7  Yaqi Qiu7  Honglin Chen8  Yuyou Duan8  Xiajing Li9  Chuxin Chen1,10  Ning Wang1,11  Zhiyong Zhong1,11  Qicong Chen1,11  Xianglian Tang1,11  Jinsong Li1,12 
[1] Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, 510180, Guangzhou, People’s Republic of China;Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, No.1 Panfu Road, 510180, Guangzhou, People’s Republic of China;Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, 510220, Guangzhou, People’s Republic of China;Department of General Surgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, 510080, Guangzhou, People’s Republic of China;Department of Hepatobiliary Pancreatic Surgery, Huadu District People’s Hospital of Guangzhou, 510800, Guangzhou, People’s Republic of China;Department of Internal Medicine, University of California Davis Medical Center, 95817, Sacramento, CA, USA;Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, No.382 Waihuan East Road, Suite 406, Higher Education Mega Center, 510006, Guangzhou, People’s Republic of China;Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, No.382 Waihuan East Road, Suite 406, Higher Education Mega Center, 510006, Guangzhou, People’s Republic of China;National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, 510006, Guangzhou, People’s Republic of China;Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, 510006, Guangzhou, People’s Republic of China;Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, 510006, Guangzhou, People’s Republic of China;Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, 510006, Guangzhou, People’s Republic of China;Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, No.382 Waihuan East Road, Suite 406, Higher Education Mega Center, 510006, Guangzhou, People’s Republic of China;School of Medicine, South China University of Technology, 510180, Guangzhou, People’s Republic of China;School of Biology and Biological Engineering, South China University of Technology, 510006, Guangzhou, People’s Republic of China;School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, 510006, Guangzhou, People’s Republic of China;Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, No.382 Waihuan East Road, Suite 406, Higher Education Mega Center, 510006, Guangzhou, People’s Republic of China;State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, 200031, Shanghai, China;University of Chinese Academy of Sciences, 200031, Shanghai, China;
关键词: Human embryonic stem cells;    Cell spheroids;    Exosomes;    Liver fibrosis;    microRNAs;    TGFβRII-SMADS pathway;   
DOI  :  10.1186/s12951-021-01138-2
来源: Springer
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【 摘 要 】

BackgroundExosomes secreted from stem cells exerted salutary effects on the fibrotic liver. Herein, the roles of exosomes derived from human embryonic stem cell (hESC) in anti-fibrosis were extensively investigated. Compared with two-dimensional (2D) culture, the clinical and biological relevance of three-dimensional (3D) cell spheroids were greater because of their higher regeneration potential since they behave more like cells in vivo. In our study, exosomes derived from 3D human embryonic stem cells (hESC) spheroids and the monolayer (2D) hESCs were collected and compared the therapeutic potential for fibrotic liver in vitro and in vivo.ResultsIn vitro, PKH26 labeled-hESC-Exosomes were shown to be internalized and integrated into TGFβ-activated-LX2 cells, and reduced the expression of profibrogenic markers, thereby regulating cellular phenotypes. TPEF imaging indicated that PKH26-labeled-3D-hESC-Exsomes possessed an enhanced capacity to accumulate in the livers and exhibited more dramatic therapeutic potential in the injured livers of fibrosis mouse model. 3D-hESC-Exosomes decreased profibrogenic markers and liver injury markers, and improved the level of liver functioning proteins, eventually restoring liver function of fibrosis mice. miRNA array revealed a significant enrichment of miR-6766-3p in 3D-hESC-Exosomes, moreover, bioinformatics and dual luciferase reporter assay identified and confirmed the TGFβRII gene as the target of miR-6766-3p. Furthermore, the delivery of miR-6766-3p into activated-LX2 cells decreased cell proliferation, chemotaxis and profibrotic effects, and further investigation demonstrated that the expression of target gene TGFβRII and its downstream SMADs proteins, especially phosphorylated protein p-SMAD2/3 was also notably down-regulated by miR-6766-3p. These findings unveiled that miR-6766-3p in 3D-hESC-Exosomes inactivated SMADs signaling by inhibiting TGFβRII expression, consequently attenuating stellate cell activation and suppressing liver fibrosis.ConclusionsOur results showed that miR-6766-3p in the 3D-hESC-Exosomes inactivates smads signaling by restraining TGFβRII expression, attenuated LX2 cell activation and suppressed liver fibrosis, suggesting that 3D-hESC-Exosome enriched-miR-6766-3p is a novel anti-fibrotic therapeutics for treating chronic liver disease. These results also proposed a significant strategy that 3D-Exo could be used as natural nanoparticles to rescue liver injury via delivering antifibrotic miR-6766-3p.Graphical Abstract

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