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Review
. 2021 Nov 15:12:785717.
doi: 10.3389/fimmu.2021.785717. eCollection 2021.

The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous

Jia-Ming Chen  1 , Qiao-Yi Huang  1 , Yun-Xia Zhao  2 , Wei-Hong Chen  1 , Shu Lin  3   4 , Qi-Yang Shi  1
Affiliations
Review

The Latest Developments in Immunomodulation of Mesenchymal Stem Cells in the Treatment of Intrauterine Adhesions, Both Allogeneic and Autologous

Jia-Ming Chen et al. Front Immunol. .

Abstract

Intrauterine adhesion (IUA) is an endometrial fibrosis disease caused by repeated operations of the uterus and is a common cause of female infertility. In recent years, treatment using mesenchymal stem cells (MSCs) has been proposed by many researchers and is now widely used in clinics because of the low immunogenicity of MSCs. It is believed that allogeneic MSCs can be used to treat IUA because MSCs express only low levels of MHC class I molecules and no MHC class II or co-stimulatory molecules. However, many scholars still believe that the use of allogeneic MSCs to treat IUA may lead to immune rejection. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, and can better adapt to the body. Here, we review recently published articles on the immunomodulation of allogeneic and autologous MSCs in IUA therapy, with the aim of proving that the use of autologous MSCs can reduce the possibility of immune rejection in the treatment of IUAs.

Keywords: allogeneic MSCs; autologous MSC; immunoregulation; intrauterine adhesion; rejection reaction.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Diagram shows the possible causes of IUA, for example uterine cavity operation, intrauterine infection, endometrial blood hypoperfusion and others.
Figure 2
Figure 2
Diagram shows the main mechanism of intrauterine adhesions, the damaged endometrium is affected by long-term antibiotic treatment, frequent sexual intercourse, vaginal flushing, decreased estrogen and other factors, which lead to the homeostasis of the internal environment changing. Broken rings in the microenvironment make bacteria easier to invade, and the damaged endometrium has an inflammatory response. On the one hand, it can release inflammatory cytokines IL-25, IL-33, TSLP, activate helper Th2 cells, and promote endometrial fibrosis. On the other hand, it can also release inflammatory cytokines TGF-β, IFN-γ, IL-6, TNF-α, etc. Among them, TGF-β can be through TGF-β-Smad5 pathway, and TNF-α and NF-κB jointly promote endometrial fibrosis, thereby forming intrauterine adhesions.
Figure 3
Figure 3
Diagram shows the release of PGE2, IDO, HGF, IL-1RA, TSG6, and TGF-β by MSCs, which stimulates macrophages to differentiate into M2 macrophages, increases anti-inflammatory cytokines IL-10, TGF-β, and arginase-1, and decreases the pro-inflammatory cytokines TNF-α, IL-12, and IL-1β, inhibiting the T cell response, and inducing regulatory T cells. In addition, when MSCs were co-cultured with macrophages, the expression levels of HLA-DR/DP/DQ and CD86 were decreased, thereby reducing the phagocytic ability and antigen presentation ability of macrophages, leading to further immunosuppression and supporting the therapeutic effect of MSCs.
Figure 4
Figure 4
Diagram showing the mechanism by which MSCs inhibit the maturation of dendritic cells, reduce the ability to activate T cells, and decrease HLA-DR, CD40, OX40L, CD80, CD83, CD86 expression, while increasing PD-L1 expression. This process causes the inhibition of CD4+ and CD8+ T cells by paracrine or cell contact. On the one hand, inhibiting CD4+ helper T cells can inhibit the binding of CD40 ligands with CD40 on the surface of dendritic cells, thereby reducing the transformation to CD8+ T cells. In addition, inhibiting CD4+ helper T cells can reduce the release of IL-2 and formation of CD8 + T cells, and ultimately reduce the release of pro-inflammatory cytokines TNF-α and IFN-γ. On the other hand, MSCs can induce the differentiation of regulatory T cells and trigger dendritic cells to promote the transformation of Th1 to Th2, resulting in a decrease of the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17 and IL-6, and an increase in the levels of the anti-inflammatory cytokines IL-4 and IL-10, which contributes to the treatment of MSCs. In addition, when dendritic cells were co-cultured with MSCs, the secretion of pro-inflammatory cytokines by CD1c+ DC decreased, and the secretion of anti-inflammatory cytokine IL-10 by plasmacytoid DC increased, which further led to immunosuppression and supported the treatment of MSCs.
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