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Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models

Cellular & Molecular Immunology (2019) | Download Citation

Abstract

Mesenchymal stem cells (MSCs), which are pluripotent cells with immunomodulatory properties, have been considered good candidates for the therapy of several immune disorders, such as inflammatory bowel diseases, concanavalin A-induced liver injury, and graft-versus-host disease. The embryo is a natural allograft to the maternal immune system. A successful pregnancy depends on the timely extinction of the inflammatory response induced by embryo implantation, followed by the switch to a tolerant immune microenvironment in both the uterus and the system. Excessive infiltration of immune cells and serious inflammatory responses are triggers for embryo rejection, which results in miscarriage. Here, we demonstrated that adoptive transfer of MSCs could prevent fetal loss in a lipopolysaccharide (LPS)-induced abortion model and immune response-mediated spontaneous abortion model. The immunosuppressive MSCs alleviated excessive inflammation by inhibiting CD4 + T cell proliferation and promoting the decidual macrophage switch to M2 in a tumor necrosis factor-stimulated gene-6 (TSG-6)-dependent manner. Cell-to-cell contact with proinflammatory macrophages increased the TSG-6 production by the MSCs, thereby enhancing the suppressive regulation of T cells and macrophages. Moreover, proinflammatory macrophages in contact with the MSCs upregulated the expression of CD200 on the stem cells and facilitated the reprogramming of macrophages towards an anti-inflammatory skew through the interaction of CD200 with CD200R on proinflammatory macrophages. Therefore, the results demonstrate that a TSG-6-mediated paracrine effect, reinforced by cell-to-cell contact between MSCs and proinflammatory macrophages, is involved in the mechanism of MSC-mediated abortion relief through the induction of immune tolerance. Our study also indicates the potential application of MSCs in clinical recurrent miscarriages.

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Acknowledgements

This work was supported by the National Basic Research Program of China (2015CB943300 and 2017YFC1001403), the Nature Science Foundation from the National Nature Science Foundation of China (NSFC) (81630036, 91542116, 31570920, 81490744, 31171437, 31270969, 81571512, and 81501334), the Innovation-oriented Science and Technology Grant from the NHC Key Laboratory of Reproduction Regulation (CX2017-2), the Program of Shanghai Academic/Technology Research Leader (17XD1400900), the Key Project of Shanghai Municipal Education Commission (MECSM) (14ZZ013), and the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission (STCSM) (12JC1401600).

Author contributions

L.Y.H., experimental design, performance of experiments and data analysis, and manuscript writing; Z.D. and X.L., performance of experiments, analysis of data, and generation of figures; Z.J., L.Y.K. and H.J.F., generation of figures and literature search; Z.Y.Y., Z.X.X. and L.D.J., study design and data interpretation; D.M.R., study design, conception of experiments and data interpretation.

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Author notes

  1. These authors contributed equally: Yanhong Li, Di Zhang, Ling Xu

Affiliations

  1. Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China

    • Yanhong Li
    • , Di Zhang
    • , Ling Xu
    • , Yikong Lin
    • , Yu Tao
    • , Dajin Li
    •  & Meirong Du
  2. Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China

    • Lin Dong
  3. Department of Immunology, Medical College of Soochow University, Suzhou, Jiangsu, China

    • Ji Zheng
  4. Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    • Jiefang Huang
    •  & Yanyun Zhang
  5. Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    • Xingxing Zang

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Meirong Du.

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https://doi.org/10.1038/s41423-019-0204-6