Abstract
IntroductionNew therapeutic options are necessary for patients with chronic Chagas disease, a leading cause of heart failure in Latin American countries. Stem cell therapy focused on improving cardiac function is a promising approach for treating heart disease. Here, we evaluated the therapeutic effects of cardiac mesenchymal stem cells (CMSCs) in a mouse model of chronic Chagas disease.MethodsCMSCs were isolated from green fluorescent protein (GFP) transgenic C57BL/6 mouse hearts and tested for adipogenic, osteogenic, chondrogenic, endothelial, and cardiogenic differentiation potentials evaluated by histochemical and immunofluorescence techniques. A lymphoproliferation assay was performed to evaluate the immunomodulatory activity of CMSCs. To investigate the therapeutic potential of CMSCs, C57BL/6 mice chronically infected with Trypanosoma cruzi were treated with 106 CMSCs or saline (control) by echocardiography-guided injection into the left ventricle wall. All animals were submitted to cardiac histopathological and immunofluorescence analysis in heart sections from chagasic mice. Analysis by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed in the heart to evaluate the expression of cytokines involved in the inflammatory response.ResultsCMSCs demonstrated adipogenic, osteogenic, and chondrogenic differentiation potentials. Moreover, these cells expressed endothelial cell and cardiomyocyte features upon defined stimulation culture conditions and displayed immunosuppressive activity in vitro. After intramyocardial injection, GFP+ CMSCs were observed in heart sections of chagasic mice one week later; however, no observed GFP+ cells co-expressed troponin T or connexin-43. Histopathological analysis revealed that CMSC-treated mice had a significantly decreased number of inflammatory cells, but no reduction in fibrotic area, two months after treatment. Analysis by qRT-PCR demonstrated that cell therapy significantly decreased tumor necrosis factor-alpha expression and increased transforming growth factor-beta in heart samples.ConclusionsWe conclude that the CMSCs exert a protective effect in chronic chagasic cardiomyopathy primarily through immunomodulation.
Highlights
New therapeutic options are necessary for patients with chronic Chagas disease, a leading cause of heart failure in Latin American countries
Morphological and phenotypical characteristics of cardiac mesenchymal stem cells Stem cells isolated from green fluorescent protein (GFP) transgenic mouse hearts had fibroblast-like morphologic characteristics of MSCs (Figure 1A)
cardiac mesenchymal stem cell (CMSC) were analyzed by flow cytometry to evaluate the expression of cell surface markers used to identify different cell populations (Figure 1E)
Summary
New therapeutic options are necessary for patients with chronic Chagas disease, a leading cause of heart failure in Latin American countries. Despite advances in clinical and surgical care of cardiac patients, current therapies are able to treat symptoms, delay clinical deterioration, and increase survival but are not effective in repair induction in a diseased heart This is the case of chronic cardiac Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi and remains a leading cause of heart failure in Latin America [1]. A major effort is under way to develop therapies aiming at regenerating the myocardium or to stimulate endogenous repair programs Different cell types, such as bone marrow cells, mesenchymal stem cells (MSCs) from adipose tissue, and skeletal myoblasts, have been tested in basic and applied clinical studies [1,2,3,4]. Different cell types are likely to have therapeutic potential in various disease settings, depending on the particular cardio-pathogenic mechanisms involved
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