Dataset Information

Regulatory T cell activation, proliferation, and reprogramming induced by extracellular vesicles.

ABSTRACT:

Background

Extracellular vesicles (EVs) from heart stromal/progenitor cells modulate innate immunity, with salutary effects in a variety of cardiac disease models. Little is known, however, about the effects of these EVs on adaptive immunity.

Methods

Ex vivo differentiation of naïve CD4⁺ T cells was conducted to assess the effect of EVs on cytokine production and proliferation of Th1, Th2, Th17, and regulatory T (T_reg) cells. These effects were further tested in vivo using the experimental autoimmune myocarditis (EAM) model.

Results

Using differentiated CD4⁺ T cells, we show that EVs secreted by human-derived heart stromal/progenitor cells selectively influence the phenotype, activity, and proliferation of regulatory T (T_reg) cells. Exposure of T_reg cells to EVs results in faster proliferation, augmented production of IL-10, and polarization toward an intermediate FOXP3⁺RORγt⁺ phenotype. In experimental autoimmune myocarditis, EVs attenuate cardiac inflammation and functional decline, in association with increased numbers of splenic IL10⁺-T_reg cells.

Conclusions

T cell modulation by EVs represents a novel therapeutic approach to inflammation, harnessing endogenous immunosuppressive mechanisms that may be applied in solid organ transplantation, graft-versus-host disease, and autoimmune disorders.

SUBMITTER: Akhmerov A

PROVIDER: S-EPMC8570987 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Regulatory T cell activation, proliferation, and reprogramming induced by extracellular vesicles.

Akhmerov Akbarshakh A Rogers Russell R de Couto Geoffrey G Valle Jackelyn J Li Liang L Ibrahim Ahmed A Sanchez Lizbeth L Zhang Rui R Lin Yen-Nien YN Liu Weixin W Marbán Eduardo E

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20210624 11

<h4>Background</h4>Extracellular vesicles (EVs) from heart stromal/progenitor cells modulate innate immunity, with salutary effects in a variety of cardiac disease models. Little is known, however, about the effects of these EVs on adaptive immunity.<h4>Methods</h4>Ex vivo differentiation of naïve CD4<sup>+</sup> T cells was conducted to assess the effect of EVs on cytokine production and proliferation of Th1, Th2, Th17, and regulatory T (T<sub>reg</sub>) cells. These effects were further tested ...[more]

PMID: 34281778

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Project description:Progression of fibrosis and the development of cirrhosis are responsible for the liver related morbidity and mortality associated with chronic liver diseases. There is currently a great unmet need for effective anti-fibrotic strategies. Stem cells play a central role in wound healing responses to restore liver homeostasis following injury. Here we tested the hypothesis that extracellular vesicles (EVs) isolated from induced pluripotent stem cells (iPSC) modulate hepatic stellate cell (HSCs) activation and may have anti-fibrotic effects. Human iPSCs were generated by reprogramming primary skin fibroblasts. EVs were isolated by differential centrifugation, quantified by flow cytometry (FACS) and characterized by dynamic light scattering (DLS) and electron microscopy (TEM). Primary human HSCs were activated with TGFβ (10 ng/mL) and exposed to iPSC-EVs. Efficacy of iPSC-EVs was tested on HSC in vitro and in two murine models of liver injury (CCl4 and bile duct ligation). Characterization of iPSC-derived EVs by flow cytometry identified a large population of EVs released by iPSC, primarily with a diameter of 300 nm and that could be visualized by TEM as round, cup-shaped objects. Fluorescent tracing assays detected iPSC-EVs in HSC cytosol after a short incubation and EV uptake by HSCs resulted in both decrease of pro-fibrogenic markers αSMA, CollagenIα1, Fibronectin and TIMP-1 and HSC pro-fibrogenic responses such as chemotaxis and proliferation. Genomics analyses of iPSC-EV miRNA cargo revealed 22 highly expressed miRNAs, among which miR-92a-3p resulted the most abundant. Transcriptome analysis identified 60 genes down-modulated and 235 up-regulated in TGF-β-primed HSC in presence or absence of iPSC-EVs. Intravenous injection of iPSC-EVs in CCl4 and bile duct ligation-induced liver fibrosis resulted in anti-fibrotic effects at protein and gene levels. Results of this study identify iPSC-EVs as a novel anti-fibrotic approach that may reduce or reverse liver fibrosis in patients with chronic liver disease.

Dataset Information

Regulatory T cell activation, proliferation, and reprogramming induced by extracellular vesicles.

Background

Methods

Results

Conclusions

Publications

Regulatory T cell activation, proliferation, and reprogramming induced by extracellular vesicles.

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