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


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.


  1. 1.

    Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008.

    Article  Google Scholar 

  2. 2.

    Kistangari G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin N Am. 2013;27:495–520.

    Article  Google Scholar 

  3. 3.

    Panitsas FP, Theodoropoulou M, Kouraklis A, Karakantza M, Theodorou GL, Zoumbos NC, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood. 2004;103:2645–7.

    CAS  Article  Google Scholar 

  4. 4.

    Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13:668–77.

    CAS  Article  Google Scholar 

  5. 5.

    Zhu X, Ma D, Zhang J, Peng J, Qu X, Ji C, et al. Elevated interleukin-21 correlated to Th17 and Th1 cells in patients with immune thrombocytopenia. J Clin Immunol. 2010;30:253–9.

    CAS  Article  Google Scholar 

  6. 6.

    Qiao J, Li X, Wu Y, Wu X, Zhu F, Liu N, et al. An increased expression profile of Th9/IL-9 correlated with Th17/IL-17 in patients with immune thrombocytopenia. Platelets. 2017;28:287–94.

    CAS  Article  Google Scholar 

  7. 7.

    Li J, Tian J, Lu J, Wang Z, Ling J, Wu X, et al. LncRNA GAS5 inhibits Th17 differentiation and alleviates immune thrombocytopenia via promoting the ubiquitination of STAT3. Int Immunopharmacol. 2020;80:106127.

    CAS  Article  Google Scholar 

  8. 8.

    Jernås M, Nookaew I, Wadenvik H, Olsson B. MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP). Blood. 2013;121:2095–8.

    Article  Google Scholar 

  9. 9.

    Garabet L, Ghanima W, Rangberg A, Teruel-Montoya R, Martinez C, Lozano ML, et al. Circulating microRNAs in patients with immune thrombocytopenia before and after treatment with thrombopoietin-receptor agonists. Platelets. 2020;31:198–205.

    CAS  Article  Google Scholar 

  10. 10.

    Afonso-Grunz F, Müller S. Principles of miRNA-mRNA interactions: beyond sequence complementarity. Cell Mol Life Sci. 2015;72:3127–41.

    CAS  Article  Google Scholar 

  11. 11.

    Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517.

    CAS  Article  Google Scholar 

  12. 12.

    Tyndall A, Uccelli A. Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks. Bone Marrow Transplant. 2009;43:821–8.

    CAS  Article  Google Scholar 

  13. 13.

    Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.

    CAS  Article  Google Scholar 

  14. 14.

    Bassi ÊJ, Moraes-Vieira PMM, Moreira-Sá CSR, Almeida DC, Vieira LM, Cunha CS, et al. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes. Diabetes. 2012;61:2534–45.

    CAS  Article  Google Scholar 

  15. 15.

    Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58:929–39.

    CAS  Article  Google Scholar 

  16. 16.

    Liang X, Ding Y, Zhang Y, Tse H-F, Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. Cell Transplant. 2014;23:1045–59.

    Article  Google Scholar 

  17. 17.

    Blazquez R, Sanchez-Margallo FM, de la Rosa O, Dalemans W, Alvarez V, Tarazona R, et al. Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front Immunol. 2014;5:556.

    Article  Google Scholar 

  18. 18.

    Qu Y, Zhang Q, Cai X, Li F, Ma Z, Xu M, et al. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J Cell Mol Med. 2017;21:2491–502.

    CAS  Article  Google Scholar 

  19. 19.

    Di T-T, Ruan Z-T, Zhao J-X, Wang Y, Liu X, Wang Y, et al. Astilbin inhibits Th17 cell differentiation and ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice via Jak3/Stat3 signaling pathway. Int Immunopharmacol. 2016;32:32–8.

    CAS  Article  Google Scholar 

  20. 20.

    Zhang X, Wang F, Wang Z, Yang X, Yu H, Si S, et al. ALKBH5 promotes the proliferation of renal cell carcinoma by regulating AURKB expression in an m(6)A-dependent manner. Ann Transl Med. 2020;8:646.

    Article  Google Scholar 

  21. 21.

    Takeda K, Sowa Y, Nishino K, Itoh K, Fushiki S. Adipose-derived stem cells promote proliferation, migration, and tube formation of lymphatic endothelial cells in vitro by secreting lymphangiogenic factors. Ann Plast Surg. 2015;74:728–36.

    CAS  Article  Google Scholar 

  22. 22.

    Yang BH, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M, et al. Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 2016;9:444–57.

    CAS  Article  Google Scholar 

  23. 23.

    Castro-Manrreza ME, Bonifaz L, Castro-Escamilla O, Monroy-García A, Cortés-Morales A, Hernández-Estévez E, et al. Mesenchymal stromal cells from the epidermis and dermis of psoriasis patients: morphology, immunophenotype, differentiation patterns, and regulation of T cell proliferation. Stem Cells Int. 2019;2019:4541797.

    CAS  Article  Google Scholar 

  24. 24.

    Vicencio JM, Yellon DM, Sivaraman V, Das D, Boi-Doku C, Arjun S, et al. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol. 2015;65:1525–36.

    CAS  Article  Google Scholar 

  25. 25.

    Ma S, Jia W, Ni S. miR-199a-5p inhibits the progression of papillary thyroid carcinoma by targeting SNAI1. Biochem Biophys Res Commun. 2018;497:181–6.

    CAS  Article  Google Scholar 

  26. 26.

    Wang Y, Dai Y-X, Wang S-Q, Qiu M-K, Quan Z-W, Liu Y-B, et al. miR-199a-5p inhibits proliferation and induces apoptosis in hemangioma cells through targeting HIF1A. Int J Immunopathol Pharmacol. 2018;31:394632017749357.

    PubMed  Google Scholar 

  27. 27.

    Li Y, Wang D, Li X, Shao Y, He Y, Yu H, et al. MiR-199a-5p suppresses non-small cell lung cancer via targeting MAP3K11. J Cancer. 2019;10:2472–9.

    CAS  Article  Google Scholar 

  28. 28.

    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    CAS  Article  Google Scholar 

  29. 29.

    Mathur AN, Chang H-C, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol. 2007;178:4901–7.

    CAS  Article  Google Scholar 

  30. 30.

    Limagne E, Thibaudin M, Euvrard R, Berger H, Chalons P, Végan F, et al. Sirtuin-1 activation controls tumor growth by impeding Th17 differentiation via STAT3 deacetylation. Cell Rep. 2017;19:746–59.

    CAS  Article  Google Scholar 

  31. 31.

    Li Z-H, Wang Y-F, He D-D, Zhang X-M, Zhou Y-L, Yue H, et al. Let-7f-5p suppresses Th17 differentiation via targeting STAT3 in multiple sclerosis. Aging. 2019;11:4463–77.

    Article  Google Scholar 

  32. 32.

    Geng W, Tang H, Luo S, Lv Y, Liang D, Kang X, et al. Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation. Am J Transl Res. 2019;11:780–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Liu J, Jiang M, Deng S, Lu J, Huang H, Zhang Y, et al. miR-93-5p-containing exosomes treatment attenuates acute myocardial infarction-induced myocardial damage. Mol Ther Nucleic Acids. 2018;11:103–15.

    CAS  Article  Google Scholar 

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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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Correspondence to 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 (2021). https://doi.org/10.1038/s41374-020-00515-z

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