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Extracellular vesicles from mesenchymal stem cells prevent contact hypersensitivity through the suppression of Tc1 and Th1 cells and expansion of regulatory T cells.

Abstract

Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSC-EVs) are taken more seriously as immunomodulatory and anti-inflammatory agents. We studied the therapeutic effects of MSC-EVs on allergic contact dermatitis (ACD), a typical T cell-mediated disorder. A contact hypersensitivity (CHS) mouse model for ACD was established and treated by intravenous MSC-EVs injection. We found that human umbilical cord MSC-EVs could significantly prevent the pathology of CHS, including reduced ear swelling and leukocyte infiltration. Injection of MSC-EVs significantly inhibited CD8+IFN-γ+ cytotoxic T (Tc1) cells and CD4+IFN-γ+ type 1 helper T (Th1) cells, and reduced the level of pro-inflammatory Tumor Necrosis Factor-alpha (TNF-α) and interferon gamma (IFN-γ), and induced CD4+CD25+Foxp3+ regulatory T cells (Tregs) and the level of anti-inflammatory IL-10. In vitro, MSC-EVs also suppressed Tc1 and Th1 cells and induced Tregs and the related cytokines, further indicating the immune regulatory role of MSC-EVs. Interestingly, PKH26-labeled MSC-EVs were found to be directly internalized by CD3+ T cells, resulting in reduced signal transducer and activator of transcription 1 (STAT1) protein levels in vitro. In summary, MSC-EVs can prevent the onset of CHS by inhibiting Tc1 and Th1 immune responses and inducing the Tregs phenotype in vivo and in vitro. The mechanism by which MSC-EVs influence CD3+ T cells might partially involve targeting STAT1 in vitro. Therefore, MSC-EVs are ideal candidates for cell-free immunomodulatory therapy for T cell-mediated diseases such as ACD.

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    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China; South China University of Technology, Guangzhou, Guangdong 510006, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China; South China University of Technology, Guangzhou, Guangdong 510006, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China.

    ,

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China; South China University of Technology, Guangzhou, Guangdong 510006, PR China. Electronic address: miyadu@hotmail.com.

    Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Geriatrics Institute, Guangzhou, Guangdong 510080, PR China; South China University of Technology, Guangzhou, Guangdong 510006, PR China. Electronic address: wengjianyu1969@163.com.

    Source

    International immunopharmacology 74: 2019 Jun 11 pg 105663

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31200338

    Citation

    Guo, Liyan, et al. "Extracellular Vesicles From Mesenchymal Stem Cells Prevent Contact Hypersensitivity Through the Suppression of Tc1 and Th1 Cells and Expansion of Regulatory T Cells." International Immunopharmacology, vol. 74, 2019, p. 105663.
    Guo L, Lai P, Wang Y, et al. Extracellular vesicles from mesenchymal stem cells prevent contact hypersensitivity through the suppression of Tc1 and Th1 cells and expansion of regulatory T cells. Int Immunopharmacol. 2019;74:105663.
    Guo, L., Lai, P., Wang, Y., Huang, T., Chen, X., Luo, C., ... Weng, J. (2019). Extracellular vesicles from mesenchymal stem cells prevent contact hypersensitivity through the suppression of Tc1 and Th1 cells and expansion of regulatory T cells. International Immunopharmacology, 74, p. 105663. doi:10.1016/j.intimp.2019.05.048.
    Guo L, et al. Extracellular Vesicles From Mesenchymal Stem Cells Prevent Contact Hypersensitivity Through the Suppression of Tc1 and Th1 Cells and Expansion of Regulatory T Cells. Int Immunopharmacol. 2019 Jun 11;74:105663. PubMed PMID: 31200338.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Extracellular vesicles from mesenchymal stem cells prevent contact hypersensitivity through the suppression of Tc1 and Th1 cells and expansion of regulatory T cells. AU - Guo,Liyan, AU - Lai,Peilong, AU - Wang,Yulian, AU - Huang,Tian, AU - Chen,Xiaomei, AU - Luo,Chenwei, AU - Geng,Suxia, AU - Huang,Xin, AU - Wu,Suijing, AU - Ling,Wei, AU - Huang,Lisi, AU - Du,Xin, AU - Weng,Jianyu, Y1 - 2019/06/11/ PY - 2019/03/26/received PY - 2019/05/05/revised PY - 2019/05/24/accepted PY - 2019/6/15/pubmed PY - 2019/6/15/medline PY - 2019/6/15/entrez KW - Allergic contact dermatitis KW - Contact hypersensitivity KW - Extracellular vesicles KW - Immunoregulation KW - Mesenchymal stem cells SP - 105663 EP - 105663 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 74 N2 - Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSC-EVs) are taken more seriously as immunomodulatory and anti-inflammatory agents. We studied the therapeutic effects of MSC-EVs on allergic contact dermatitis (ACD), a typical T cell-mediated disorder. A contact hypersensitivity (CHS) mouse model for ACD was established and treated by intravenous MSC-EVs injection. We found that human umbilical cord MSC-EVs could significantly prevent the pathology of CHS, including reduced ear swelling and leukocyte infiltration. Injection of MSC-EVs significantly inhibited CD8+IFN-γ+ cytotoxic T (Tc1) cells and CD4+IFN-γ+ type 1 helper T (Th1) cells, and reduced the level of pro-inflammatory Tumor Necrosis Factor-alpha (TNF-α) and interferon gamma (IFN-γ), and induced CD4+CD25+Foxp3+ regulatory T cells (Tregs) and the level of anti-inflammatory IL-10. In vitro, MSC-EVs also suppressed Tc1 and Th1 cells and induced Tregs and the related cytokines, further indicating the immune regulatory role of MSC-EVs. Interestingly, PKH26-labeled MSC-EVs were found to be directly internalized by CD3+ T cells, resulting in reduced signal transducer and activator of transcription 1 (STAT1) protein levels in vitro. In summary, MSC-EVs can prevent the onset of CHS by inhibiting Tc1 and Th1 immune responses and inducing the Tregs phenotype in vivo and in vitro. The mechanism by which MSC-EVs influence CD3+ T cells might partially involve targeting STAT1 in vitro. Therefore, MSC-EVs are ideal candidates for cell-free immunomodulatory therapy for T cell-mediated diseases such as ACD. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/31200338/Extracellular_vesicles_from_mesenchymal_stem_cells_prevent_contact_hypersensitivity_through_the_suppression_of_Tc1_and_Th1_cells_and_expansion_of_regulatory_T_cells L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(19)30624-1 DB - PRIME DP - Unbound Medicine ER -