Mesenchymal Stem/Stromal Cells Protect against Autoimmunity via CCL2-Dependent Recruitment of Myeloid-Derived Suppressor Cells

Lee, Hyun Ju; Ko, Jung Hwa; Jeong, Hyun Jeong; Ko, Ah Young; Kim, Mee Kum; Wee, Won Ryang; Yoon, Sun Woo; Oh, Joo Youn

doi:10.4049/jimmunol.1402139

Cited by 61 publications

(65 citation statements)

References 63 publications

(67 reference statements)

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“…MSCs ameliorate experimental autoimmune uveitis via recruiting myeloid-derived suppressor cells in a CCL2-dependent manners41. Overall these studies indicate that MSCs produce CCL2 for various immune cell recruitment and secrete CCL2 variant for direct inhibition of immune cells.…”

Section: Discussionmentioning

confidence: 68%

CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms

Lee

Kim

et al. 2017

Sci Rep

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Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production. Mesenchymal stem cells (MSCs) ameliorate SLE symptoms by targeting T cells, whereas the mechanisms of their efficacy remain incompletely understood. In this study, we show that transfer of human MSCs increased MRL.Faslpr mouse survival, decreased T cell infiltration in the kidneys, and reduced T cell cytokine expression. In vitro, allogeneic mouse MSCs inhibited MRL.Faslpr T cell proliferation and cytokine production. Time-lapse imaging revealed that MSCs recruited MRL.Faslpr T cells establishing long-lasting cellular contacts by enhancing T cell VCAM-1 expression in a CCL2-dependent manner. In contrast, CCL2 deficient MSCs did not induce T cell migration and VCAM-1 expression, resulting in insufficient cell-cell contact. Consequently, CCL2 deficient MSCs did not inhibit IFN-γ production by T cells and upon transfer no longer prolonged survival of MRL.Faslpr mice. Taken together, our imaging study demonstrates that CCL2 enables the prolonged MSC–T cell interactions needed for sufficient suppression of autoreactive T cells and helps to understand how MSCs ameliorate symptoms in lupus-prone MRL.Faslpr mice.

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Section: Discussionmentioning

confidence: 68%

CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms

Lee

Kim

et al. 2017

Sci Rep

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“…MSCs administered systemically in inflamed mice can migrate to the draining lymph nodes and spleen where increased number of regulatory myeloid and lymphoid cells efficiently controls the progression of inflammation (28, 45). Additionally, the navigation of native MSCs, mobilized from adipose tissue, through the lymph fluid homing into active lymph nodes has been reported (27).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical models of arthritis and colitis using human eASCs allowed dissection of pathways shared by the human and mouse systems (28, 48–50). Moreover, we have recently shown that eASCs are short-lived after in vivo administration (40), even when used in a syngeneic setting (8), indicating that eASCs, regardless the MHC context, can prime host immune cells thorough an array of not fully understood specific molecular mechanisms, which, in turn, adopt a regulatory phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…The intraperitoneal route is mainly restricted to preclinical studies. Interestingly, previous studies have demonstrated that systemically administered MSCs homed to lymphoid tissues associated with the inflammatory site where functional MSC-induced immune cells with regulatory phenotype (i.e., regulatory T cells) were increased, mediating the immunomodulatory effects of MSCs (10, 11, 27, 28). …”

Section: Introductionmentioning

confidence: 99%

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Intralymphatic Administration of Adipose Mesenchymal Stem Cells Reduces the Severity of Collagen-Induced Experimental Arthritis

et al. 2017

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Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunomodulatory properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Previous studies have demonstrated that MSCs, administered systemically, migrate to lymphoid tissues associated with the inflammatory site where functional MSC-induced immune cells with a regulatory phenotype were increased mediating the immunomodulatory effects of MSCs. These results suggest that homing of MSCs to the lymphatic system plays an important role in the mechanism of action of MSCs in vivo. Thus, we hypothesized that direct intralymphatic (IL) (also referred as intranodal) administration of MSCs could be an alternative and effective route of administration for MSC-based therapy. Here, we report the feasibility and efficacy of the IL administration of human expanded adipose mesenchymal stem cells (eASCs) in a mouse model of collagen-induced arthritis (CIA). IL administration of eASCs attenuated the severity and progression of arthritis, reduced bone destruction and increased the levels of regulatory T cells (CD25+Foxp3+CD4+ cells) and Tr1 cells (IL10+CD4+), in spleen and draining lymph nodes. Taken together, these results indicate that IL administration of eASCs is very effective in modulating established CIA and may represent an alternative treatment modality for cell therapy with eASCs.

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“…12-0247-C1A0 and 13-0104-C3A0). EAU was induced as we previously reported (36). Corneal transplantation was performed as we previously described (5).…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

Lee

Jeong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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135

109

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Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-α-stimulated gene/protein (TSG)-6-dependent manner. As a result, mice were protected against subsequent immune challenge in two models of alloand autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell-suppressive activities independently of FoxP3 + regulatory T cells. Adoptive transfer of MSCinduced B220 + CD11b + monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II + B220 + CD11b + cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages. corneal allotransplantation | experimental autoimmune uveitis | immune tolerance | mesenchymal stem/stromal cell | monocyte/macrophage

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Mesenchymal Stem/Stromal Cells Protect against Autoimmunity via CCL2-Dependent Recruitment of Myeloid-Derived Suppressor Cells

Cited by 61 publications

References 63 publications

CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms

CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms

Intralymphatic Administration of Adipose Mesenchymal Stem Cells Reduces the Severity of Collagen-Induced Experimental Arthritis

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

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