Mesenchymal stem cells prevent overwhelming inflammation and reduce infection severity via recruiting CXCR3<sup>+</sup> regulatory T cells

Li, Wenchao; Chen, Weiwei; Huang, Saisai; Yao, Genhong; Tang, Xiaojun; Sun, Lingyun

doi:10.1002/cti2.1181

Cited by 18 publications

(19 citation statements)

References 48 publications

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“…Mesenchymal stem cells (MSCs) hold great promise as a feasible and effective biological treatment for inflammation-related diseases [ 11 , 12 ]. MSCs have been shown to elicit immunomodulatory and tissue repair effects in lung inflammatory diseases, including reducing airway inflammation and ameliorating lung function [ 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization

et al. 2021

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Background Severe, steroid-resistant asthma (SSRA) is a serious clinical problem in asthma management. Affected patients have severe clinical symptoms, worsened quality of life, and do not respond to steroid, a mainstay steroid treatment of asthma. Thus, effective therapies are urgently needed. Exosomes derived from mesenchymal stem cell (MSC-Exo) has become attractive candidates for the lung inflammatory diseases through its immunomodulatory effects. In this study, we explored the therapeutic effects of MSC-Exo in SSRA and identified the therapeutic mechanism of MSC-Exo. Method Exosomes from human umbilical cord mesenchymal stem cell (hUCMSC) were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis and flow cytometry analysis. Effects of MSC-Exo on airway hyper responsiveness (AHR), inflammation, histopathology, and macrophage polarization in SSRA in mice were evaluated. Systematic depletion of macrophages determined the role of macrophages in the therapeutic effect of SSRA in mice. LPS-stimulated RAW 264.7 cell model was constructed to determine the underlying mechanism of MSC-Exo on macrophage polarization. qRT-PCR, Western blotting, immunofluorescence, and flow cytometry were performed to evaluate the expression of M1 or M2 markers. Tandem mass tags (TMT)-labeled quantitative proteomics were applied to explore the central protein during the regulation effect of MSC-Exo on macrophage polarization. Knockdown and overexpression of TRAF1 were used to further clarify the role of the central protein on macrophage polarization. Result We successfully isolated and characterized exosomes from hUCMSCs. We verified that the intratracheal administration of MSC-Exo reversed AHR, histopathology changes, and inflammation in SSRA mice. Systematic depletion of macrophages weakened the therapeutic effect of MSC-Exo. We found that MSC-Exo treatment inhibited M1 polarization and promoted M2 polarization in LPS-stimulated RAW 264.7 cells. Subsequently, tumor necrosis factor receptor-associated factor 1 (TRAF1) was determined as the central protein which may be closely related to the regulation of macrophage polarization from TMT-labeled quantitative proteomics analysis. Knockdown and overexpression of TRAF1 demonstrated that the effect of MSC-Exo treatment on macrophage polarization, NF-κB and PI3K/AKT signaling was dependent on TRAF1. Conclusion MSC-Exo can ameliorate SSRA by moderating inflammation, which is achieved by reshaping macrophage polarization via inhibition of TRAF1.

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Section: Introductionmentioning

confidence: 99%

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization

et al. 2021

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“…A recent study confirmed that the promotion of Tregs arises from an epigenetic conversion of conventional T cells to Tregs rather than expansion of natural Tregs ( Azevedo et al, 2020 ). In a murine model of respiratory infection, UC-MSCs were shown to be engulfed by lung phagocytes, which then secreted C-X-C motif ligand (CXCL)9 and CXCL10, leading to the recruitment of particularly suppressive C-X-C motif receptor (CXCR)3 + Tregs ( Li et al, 2020a ). In addition to T helper cells, MSCs also significantly impair the IFN-γ production and cytotoxic activity of CTLs ( Maccario et al, 2005 ; Malcherek et al, 2014 ).…”

Section: Regulation Of Adaptive Immunity By Mscsmentioning

confidence: 99%

Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update

Müller

Tunger

Wobus

et al. 2021

Front. Cell Dev. Biol.

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Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the pathogenesis of inflammatory disorders. Thus, MSCs efficiently impair the phagocytic and antigen-presenting capacity of monocytes/macrophages and promote the expression of immunosuppressive molecules such as interleukin (IL)-10 and programmed cell death 1 ligand 1 by these cells. They also effectively inhibit the maturation of dendritic cells and their ability to produce proinflammatory cytokines and to stimulate potent T-cell responses. Furthermore, MSCs inhibit the generation and proinflammatory properties of CD4+ T helper (Th)1 and Th17 cells, while they promote the proliferation of regulatory T cells and their inhibitory capabilities. MSCs also impair the expansion, cytokine secretion, and cytotoxic activity of proinflammatory CD8+ T cells. Moreover, MSCs inhibit the differentiation, proliferation, and antibody secretion of B cells, and foster the generation of IL-10-producing regulatory B cells. Various cell membrane-associated and soluble molecules essentially contribute to these MSC-mediated effects on important cellular components of innate and adaptive immunity. Due to their immunosuppressive properties, MSCs have emerged as promising tools for the treatment of inflammatory disorders such as acute graft-versus-host disease, graft rejection in patients undergoing organ/cell transplantation, and autoimmune diseases.

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“…Li et al observed a significant increase in CXCR3+ Tregs in the lungs and lymphoid tissues post-MSC infusion. MSCs also increased the production of CXCL9 and CXCL10 produced by lung phagocytes which mediate the recruitment of Tregs [ 34 ].…”

Section: Mesenchymal Stem Cell Therapy To Reverse Aging Effects On the Immune Systemmentioning

confidence: 99%

“…Therefore, ex vivo expansion of MSCs and subsequent administration of optimized dosage is necessary to maintain and boost the effects of MSCs in vivo [ 32 ]. Furthermore, numerous in vivo and in vitro studies have proven that MSCs have low immunogenicity, excellent immunomodulatory function, and homing capability to regenerate damaged tissues through multipotent differentiation and paracrine secretion [ 11 , 33 , 34 , 35 , 36 ]. Despite that, the current studies are not primarily focused on aging or the restoration of the immune system.…”

Section: Introductionmentioning

confidence: 99%

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System

Yeo

Nordin

et al. 2021

IJMS

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Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.

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Mesenchymal stem cells prevent overwhelming inflammation and reduce infection severity via recruiting CXCR3⁺ regulatory T cells

Abstract: MSCs recruit CXCR3 + Tregs to prevent infection W Li et al.

Cited by 18 publications

References 48 publications

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization

Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System

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Mesenchymal stem cells prevent overwhelming inflammation and reduce infection severity via recruiting CXCR3+ regulatory T cells

Abstract: MSCs recruit CXCR3 + Tregs to prevent infection W Li et al.

Cited by 18 publications

References 48 publications

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization

Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System

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Mesenchymal stem cells prevent overwhelming inflammation and reduce infection severity via recruiting CXCR3⁺ regulatory T cells