Intramyocardial transplantation of cardiac mesenchymal stem cells reduces myocarditis in a model of chronic Chagas disease cardiomyopathy

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.

The Rising Role of Mesenchymal Stem Cells in the Treatment of Various Infectious Complications

“…Transplantation of MSCs has shown clinical efficacy in animal or mouse models but studies in humans have not shown equivalent success due to a number of challenges that need to be overcome [2,91,93,95,98]. In animal models of chronic Chagas CMP, cardiac MSCs have been shown to exert protective effects by decreasing the degrees of fibrosis and inflammatory infiltrates in the affected myocardium [99]. The beneficial effects of MSC therapy in Chagas mice models may be an indirect action of the cells on the heart rather than a direct action of the large numbers of transplanted MSCs on the myocardium [91,96].…”

“…Tracking of infused BM-MSCs in animal models has shown migration of these cells to the heart and their participation in tissue repair or regeneration [91][92][93]. Although an early clinical trial of intracoronary injection of autologous BM-cells in patients with chronic Chagas CMP and heart failure showed safety and feasibility, a large multicenter, randomized double-blind, placebo-controlled trial using intracoronary infusion of BMmononuclear cells showed no improvement in cardiac function or in quality of life in patients with chronic Chagas CMP [2,99,100].…”

Tolerogenic Dendritic Cells Reduce Cardiac Inflammation and Fibrosis in Chronic Chagas Disease

“…Alternative treatments are needed, with the aim of reducing morbidity and mortality, and providing a better quality of life for the patients with CCC. Therapeutic alternatives focused on reducing the immunological mechanisms, which are key factors in the pathogenesis of the disease, modulating both inflammation and fibrosis in the heart of the patients, are of great interest (10)(11)(12)(13)(14)(15)(16).…”

Mesenchymal stem cells as the near future of cardiology medicine - truth or wish?

“…Cardiac diseases remain a major cause of worldwide morbidity and mortality 1 . In the United States of America every 34 seconds somebody suff ers a coronary event 2 .…”