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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Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008.
Kistangari G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin N Am. 2013;27:495–520.
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.
Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13:668–77.
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.
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.
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.
Jernås M, Nookaew I, Wadenvik H, Olsson B. MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP). Blood. 2013;121:2095–8.
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.
Afonso-Grunz F, Müller S. Principles of miRNA-mRNA interactions: beyond sequence complementarity. Cell Mol Life Sci. 2015;72:3127–41.
Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517.
Tyndall A, Uccelli A. Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks. Bone Marrow Transplant. 2009;43:821–8.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
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.
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.
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.
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.
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.
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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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