Extracellular vesicles derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells alleviate immune thrombocytopenia by inhibiting T helper 17 differentiation

Laboratory Investigation volume 101, pages318–327(2021)Cite this article

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Abstract

The abnormal differentiation of T helper 17 (Th17) cells is considered a vital promoter of immune thrombocytopenia (ITP) progression. Therefore, this study investigated the role of miR-199a-5p in Th17 differentiation and determined whether extracellular vesicles (EVs) derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells (ADSCs) could relieve ITP by inhibiting Th17 differentiation. The miR-199a-5p level was lessened in the spleen tissues of mice with ITP, while the signal transducer and activator of transcription 3 (STAT3) expression and the population of Th17 in CD4+T cells were boosted. Functionally, miR-199a-5p overexpression lowered IL-17 secretion and the proportion of Th17/CD4+T cells. Further investigation showed that miR-199a-5p directly targeted STAT3 mRNA, and negatively modulated its expression. STAT3 overexpression was found to facilitate Th17 differentiation, which was subsequently abolished by miR-199a-5p overexpression. EVs isolated from miR-199a-5p-modified ADSCs (miR-199a-5p-EVs) highly expressed miR-199a-5p and could restrain CD4+T cells polarized toward a Th17 phenotype in vitro. Administering of miR-199a-5p-EVs elevated platelet counts and decreased the proportion of Th17/CD4+T cells in mice with ITP. Taken together, EVs derived from miR-199a-5p-modified ADSCs vividly repressed Th17 differentiation by transferring miR-199a-5p to CD4+T cells, thus ameliorating experimental ITP.

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Fig. 1: The proportion of Th17/CD4+T cells was boosted, and the miR-199a-5p expression was lessened in the immune thrombocytopenia (ITP) mice model.
Fig. 2: miR-199a-5p overexpression restrained Th17 cell differentiation.
Fig. 3: miR-199a-5p overexpression repressed Th17 cell differentiation through targeting STAT3.
Fig. 4: miR-199a-5p-modified ADSCs package miR-199a-5p into secreted extracellular vesicles (EVs).
Fig. 5: miR-199a-5p-EVs restrained Th17 cell differentiation in CD4+T cells.
Fig. 6: miR-199a-5p-EVs reduced Th17 cell differentiation in ITP mice.

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81770115) and the Suzhou Science and Technology Plan Project (Grant No. SZS201808).

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Affiliations

  1. Hematology Department, The Children’s Hospital of Soochow University, Suzhou, 215000, China

    Jianqin Li, Yanlin Xia, Xiaoru Fan, Xiaofang Wu, Feiyun Yang & Shaoyan Hu

  2. The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, 215000, China

    Zhaoyue Wang

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  1. Jianqin Li
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Li, J., Xia, Y., Fan, X. et al. Extracellular vesicles derived from miR-199a-5p-modified adipose-derived mesenchymal stem cells alleviate immune thrombocytopenia by inhibiting T helper 17 differentiation. Lab Invest 101, 318–327 (2021). https://doi.org/10.1038/s41374-020-00515-z

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