Trypanosoma cruzi activates mouse cardiac fibroblasts in vitro leading to fibroblast-myofibroblast transition and increase in expression of extracellular matrix proteins

Coelho, Laura Lacerda; Pereira, Isabela Resende; Pereira, Mirian Claudia de Souza; Mesquita, Liliane Batista de; Lannes-Vieira, Joseli; Adesse, Daniel; Garzoni, Luciana Ribeiro

doi:10.1186/s13071-018-2614-1

Cited by 17 publications

(12 citation statements)

References 42 publications

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“…In the context of cardiac diseases, progressive fibrosis is associated with increased collagen content in the myocardium and reduced contractile function [ 24 ]. Type I Collagen is a primary constituent of the ECM [ 25 ], and T. cruzi infection activates mouse cardiac fibroblasts, increasing the expression of ECM [ 26 ]. In mammals, collagen genes are responsive to TGFβ1 [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease

Nonaka

Sampaio

França

et al. 2021

IJMS

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Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with T. cruzi and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFβ1) and T. cruzi stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of T. cruzi-infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC.

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Section: Discussionmentioning

confidence: 99%

Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease

Nonaka

Sampaio

França

et al. 2021

IJMS

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“…Moreover, increased fibronectin deposition was observed in the heart tissue of CCM individuals ( Waghabi et al., 2009 ), thus in agreement with our present results. Similarly, within the myocardium of mice infected with T. cruzi , an enhancement of fibronectin and other ECM components was detected, overlapping with the accumulation of the inflammatory infiltrate ( Pereira et al., 2014 ; Coelho et al., 2018 ). In the transwell migration assays, the combination of fibronectin with TNF-α induced an increase in the migratory response of lymphocytes from patients with Chagas disease, revealing the functional relationship between cytokines and ECM proteins such as fibronectin.…”

Section: Discussionmentioning

confidence: 82%

Enhanced Migratory Capacity of T Lymphocytes in Severe Chagasic Patients Is Correlated With VLA-4 and TNF-α Expression

Berbert

González

Villar

et al. 2021

Front. Cell. Infect. Microbiol.

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Trypanosoma cruzi infection in humans leads to progression to chronic chagasic myocarditis (CCM) in 30% of infected individuals, paralleling T cell inflammatory infiltrates in the heart tissue. T-cell trafficking into the hearts of CCM patients may be modulated by in situ expression of chemotactic or haptotactic molecules, as the chemokine CXCL12, the cytokine tumor necrosis factor-alpha (TNF-α), and extracellular matrix proteins (ECM), such as fibronectin. Herein we evaluated the expression of fibronectin, CXCL12, and TNF-α in the myocardial tissue of T. cruzi seropositive (asymptomatic or with CCM), as well as seronegative individuals as healthy controls. Hearts from CCM patients exhibited enhanced expression of these three molecules. CXCL12 and TNF-α serum levels were also increased in CCM individuals. We then evaluated T lymphocytes from chronic chagasic patients by cytofluorometry, in terms of membrane expression levels of molecules involved in cell activation and cell migration, respectively, HLA-DR and the VLA-4 (very late antigen-4, being one integrin-type fibronectin receptor). Indeed, the expression of HLA-DR and VLA-4 was enhanced on T lymphocytes from chagasic patients, especially in the CCM group. To further approach the dynamics of T cell migratory events, we performed fibronectin-, TNF-α-, and CXCL12-driven migration. Peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients presented an ex vivo enhanced migratory capacity driven by fibronectin alone when this ECM protein was placed in the membrane of transwell migration chambers. When TNF-α was previously placed upon fibronectin, we observed a further and significant increase in the migratory response of both PBMCs and T lymphocytes. Overall, these data suggest the existence in patients with chronic Chagas disease of a cardiac inflammatory infiltrate vector that promotes the recruitment and accumulation of activated T cells, driven in part by enhanced tissue expression of fibronectin and TNF-α, as well as the respective corresponding VLA-4 and TNF receptors.

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“…54,[56][57][58] Tuberculosis infection can lead to the development of pulmonary fibrosis, whereas T cruzi infection can lead to the development of cardiac fibrosis. [59][60][61] Microbial polyphosphate may therefore be a source of this fibrosis-inducing activity, which warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…In M tuberculosis , polyphosphate plays roles in infection persistence, survival, and virulence, while in T cruzi , polyphosphate is important for environmental stress adaptation 54,56‐58 . Tuberculosis infection can lead to the development of pulmonary fibrosis, whereas T cruzi infection can lead to the development of cardiac fibrosis 59‐61 . Microbial polyphosphate may therefore be a source of this fibrosis‐inducing activity, which warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Platelet polyphosphate induces fibroblast chemotaxis and myofibroblast differentiation

Suess

Smith

Morrissey

2020

Journal of Thrombosis and Haemostasis

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Background: Platelets secrete many pro-wound healing molecules such as growth factors and cytokines. We found that releasates from activated human platelets induced the differentiation of cultured murine and human fibroblasts into a myofibroblast phenotype. Surprisingly, most of this differentiation-inducing activity was heat-stable, suggesting it was not due to the protein component of the releasates. Inorganic polyphosphate is a major constituent of platelet-dense granules and promotes blood coagulation and inflammation. Objectives: We aim to investigate the contribution of polyphosphate on myofibroblast differentiating activity of platelet releasates. Methods: Using NIH-3T3 cells and primary human fibroblasts, we examined the effect of human platelet releasates and chemically synthesized polyphosphate on fibroblast differentiation and migration. Results: We found that the myofibroblast-inducing activity of platelet releasates was severely attenuated after incubation with a polyphosphate-degrading enzyme, and that fibroblasts responded to platelet-sized polyphosphate by increased levels of α-smooth muscle actin, stress fibers, and collagen. Furthermore, fibroblasts were chemotactic toward polyphosphate. Conclusions: These findings indicate that platelet-derived polyphosphate acts as a cell signaling molecule by inducing murine and human fibroblasts to differentiate into myofibroblasts, a cell type known to drive both wound healing and fibrosing diseases. Polyphosphate therefore not only promotes early wound responses through enhancing fibrin clot formation, but also may play roles in the later stages of wound healing, and, potentially, progression of fibrotic diseases, by recruiting fibroblasts and inducing their differentiation into myofibroblasts.

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Trypanosoma cruzi activates mouse cardiac fibroblasts in vitro leading to fibroblast-myofibroblast transition and increase in expression of extracellular matrix proteins

Cited by 17 publications

References 42 publications

Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease

Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease

Enhanced Migratory Capacity of T Lymphocytes in Severe Chagasic Patients Is Correlated With VLA-4 and TNF-α Expression

Platelet polyphosphate induces fibroblast chemotaxis and myofibroblast differentiation

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