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

Yanhong Li, Di Zhang, Ling Xu, Lin Dong, Ji Zheng, Yikong Lin, Jiefang Huang, Yanyun Zhang, Yu Tao, Xingxing Zang, Dajin Li, Meirong Du

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalCellular and Molecular Immunology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Mesenchymal Stromal Cells
Macrophages
Tumor Necrosis Factor-alpha
Spontaneous Abortion
Embryonic Structures
Genes
T-Lymphocytes
Habitual Abortion
Immune Tolerance
Adoptive Transfer
Induced Abortion
Immune System Diseases
Graft vs Host Disease
Immunosuppressive Agents
Concanavalin A
Inflammatory Bowel Diseases
Uterus
Allografts
Lipopolysaccharides
Immune System

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models. / Li, Yanhong; Zhang, Di; Xu, Ling; Dong, Lin; Zheng, Ji; Lin, Yikong; Huang, Jiefang; Zhang, Yanyun; Tao, Yu; Zang, Xingxing; Li, Dajin; Du, Meirong.

In: Cellular and Molecular Immunology, 01.01.2019.

Research output: Contribution to journalArticle

Li, Yanhong ; Zhang, Di ; Xu, Ling ; Dong, Lin ; Zheng, Ji ; Lin, Yikong ; Huang, Jiefang ; Zhang, Yanyun ; Tao, Yu ; Zang, Xingxing ; Li, Dajin ; Du, Meirong. / Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models. In: Cellular and Molecular Immunology. 2019.
@article{ac531bb7f9b24bf7a09511183d8fe365,
title = "Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models",
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.",
author = "Yanhong Li and Di Zhang and Ling Xu and Lin Dong and Ji Zheng and Yikong Lin and Jiefang Huang and Yanyun Zhang and Yu Tao and Xingxing Zang and Dajin Li and Meirong Du",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41423-019-0204-6",
language = "English (US)",
journal = "Cellular and Molecular Immunology",
issn = "1672-7681",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Cell–cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models

AU - Li, Yanhong

AU - Zhang, Di

AU - Xu, Ling

AU - Dong, Lin

AU - Zheng, Ji

AU - Lin, Yikong

AU - Huang, Jiefang

AU - Zhang, Yanyun

AU - Tao, Yu

AU - Zang, Xingxing

AU - Li, Dajin

AU - Du, Meirong

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85061696811&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061696811&partnerID=8YFLogxK

U2 - 10.1038/s41423-019-0204-6

DO - 10.1038/s41423-019-0204-6

M3 - Article

JO - Cellular and Molecular Immunology

JF - Cellular and Molecular Immunology

SN - 1672-7681

ER -