IFN-γ promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b

• Published in: Cell death & disease 2020-07, Vol.11 (7), p.603, Article 603
• Main Authors: Yang, Ruili, Huang, Huaming, Cui, Shengjie, Zhou, Yikun, Zhang, Ting, Zhou, Yanheng
• Format: Article
• Language: English
• Subjects: 631/80/304; 692/308/2171; Animals; Antagomirs - pharmacology; Antibodies; Base Sequence; Biochemistry; Biomedical and Life Sciences; Bone marrow; Cell Biology; Cell Culture; Cell differentiation; Cell Differentiation - drug effects; Colitis; Colitis - genetics; Colitis - pathology; Colitis - therapy; Exocytosis; Exosomes; Exosomes - drug effects; Exosomes - metabolism; Exosomes - ultrastructure; Female; Helper cells; Immunofluorescence; Immunology; Immunomodulation; Inflammatory bowel disease; Interferon-gamma - pharmacology; Life Sciences; Lymphocytes T; Mesenchymal stem cells; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - ultrastructure; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Models, Biological; Stat3 protein; STAT3 Transcription Factor - metabolism; Stem cell transplantation; Stem cells; T-Lymphocytes, Regulatory - drug effects; Th17 Cells - drug effects; γ-Interferon
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02788-0

Bone marrow mesenchymal stem cells (MSCs) have demonstrated therapeutic effects for colitis through immunomodulation and anti-inflammation. However, whether MSC-derived exosomes possessed the similar function remains unclear. In present study, exosomes were isolated from control and IFN-γ-primed MSCs and was verified by transmission electron microscope (TEM) and immunofluorescence staining. Administration of exosomes to mice significantly improved the disease activity index and histological score of colitis, and decreased the ratio of Th17 cells with elevated Treg cells ratio in mice colitis model. Exosomes from IFN-γ-primed MSCs showed superior therapeutic effects to colitis. Exosomes treatment inhibited Th17 differentiation in vitro, and exosomes from IFN-γ-primed MSCs showed higher inhibition efficacy. Mechanistically, exosomes treatment significantly decreased the expression of Stat3 and p-Stat3 to inhibit Th17 cells differentiation. IFN-γ pretreatment increased the level of miR-125a and miR-125b of exosomes, which directly targeted on Stat3, to repress Th17 cell differentiation. Moreover, combination of miR-125a and miR-125b agmior infusion also showed therapeutic effects for colitis, accompanied by decreased Th17 cell ratio. Collectively, this study demonstrates that IFN-γ treatment promoted exosomes from MSCs to attenuate colitis through increasing the level of miR-125a and miR-125b, which binding on 3′-UTR of Stat3 to repress Th17 cell differentiation. This study provides a new approach of exocytosis on the treatment of colitis.