Adipose Tissue-Derived Mesenchymal Stromal Cells Protect Mice Infected with Trypanosoma cruzi from Cardiac Damage through Modulation of Anti-parasite Immunity

Abstract

BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi (T.cruzi), is a complex disease endemic in Central and South America. It has been gathering interest due to increases in non-vectorial forms of transmission, especially in developed countries. The objective of this work was to investigate if adipose tissue-derived mesenchymal stromal cells (ASC) can alter the course of the disease and attenuate pathology in a mouse model of chagasic cardiomyopathy.Methodology/Principal FindingsASC were injected intraperitoneally at 3 days post-infection (dpi). Tracking by bioluminescence showed that cells remained in the abdominal cavity for up to 9 days after injection and most of them migrated to the abdominal or subcutaneous fat, an early parasite reservoir. ASC injection resulted in a significant reduction in blood parasitemia, which was followed by a decrease in cardiac tissue inflammation, parasitism and fibrosis at 30 dpi. At the same time point, analyses of cytokine release in cells isolated from the heart and exposed to T. cruzi antigens indicated an anti-inflammatory response in ASC-treated animals. In parallel, splenocytes exposed to the same antigens produced a pro-inflammatory response, which is important for the control of parasite replication, in placebo and ASC-treated groups. However, splenocytes from the ASC group released higher levels of IL-10. At 60 dpi, magnetic resonance imaging revealed that right ventricular (RV) dilation was prevented in ASC-treated mice.Conclusions/SignificanceIn conclusion, the injection of ASC early after T. cruzi infection prevents RV remodeling through the modulation of immune responses. Lymphoid organ response to the parasite promoted the control of parasite burden, while the heart, a target organ of Chagas disease, was protected from damage due to an improved control of inflammation in ASC-treated mice.

Galectin-3 Knockdown Impairs Survival, Migration, and Immunomodulatory Actions of Mesenchymal Stromal Cells in a Mouse Model of Chagas Disease Cardiomyopathy

“…The ability of transplanted MSC to decrease cardiac inflammation in experimental T. cruzi infected mice was shown before in studies that applied systemic and local delivery routes for cell transplantation [14–16, 35]. Here, we demonstrated that transplanted MSC caused downregulation of inflammatory cytokines directly involved in the disease pathogenesis, such as TNF- α and IFN- γ [13].…”

Resveratrol Reverses Functional Chagas Heart Disease in Mice

“…In previous studies, B-mode images were found to be more adequate to assess the geometry of chagasic hearts [32]. Before treatment (60 dpi), infected mice (INF) presented decreased left ventricle ejection fraction (LVEF), stroke volume, and cardiac output (Fig 2A), as well as dilated RV when compared with NI (S4A Fig).…”

Effects of Bone Marrow Mesenchymal Stromal Cell Therapy in Experimental Cutaneous Leishmaniasis in BALB/c Mice Induced by Leishmania amazonensis

“…Several studies have shown that MSC cells contribute in a paracrine way in tissue remodeling and control of inflammation ( 22 ). This is observed in parasitic diseases like T. cruzi ( 11 , 12 , 23 ) and Schistosoma japonicum ( 24 ). In some cases, it may have a direct effect, such as in the elimination of bacteria by inducing antimicrobial molecules, such aslipocalin 2, in the treatment of pneumonia caused by Escherichia coli infection ( 25 ), or by increasing ( 26 ) or employing IFN-gamma-activated MSCs that induce GTPases and guanylate-binding proteins that exhibit anti-parasitic action against Toxoplasma gondii and Neospora caninum ( 27 ).…”

“…These factors can inhibit apoptosis, stimulate proliferation, promote vascularization, and modulate the immune response, promoting tissue regeneration ( 7 ). Stem cell therapy showed beneficial effects in cardiomyopathies ( 8 , 9 ), including experimental chagasic cardiomyopathy caused by Trypanosoma cruzi protozoan ( 10 – 12 ). Therefore, since MSCs mitigate the progression of Chagas Disease ( 10 – 12 ), we hypothesized that it may also act on another parasites, such as L. amazonensis .…”