BACKGROUND: The hallmark of Trypanosoma cruzi infection is cardiomyopathy that leads to end-stage heart failure. We investigated whether G-CSF, known to induce heart tissue repair by bone marrow stem cell mobilization, ameliorates T. cruzi-induced myocarditis. METHODS AND RESULTS: T. cruzi-infected C3H/He mice were treated with G-CSF and monitored for parasite burden, BMSC mobilization, cytokine profile and cardiac remodeling. G-CSF increased the expression of CXCR4, CD34, and c-Kit, indicating mobilization and migration of BMSC, some of which differentiated to cardiomyocytes as evidenced by increased levels of GATA4(+)/MEF2C(+) cells and desmin expression in chagasic hearts. G-CSF enhanced a mixed cytokine response (IL-10+TGF-β>IFN-γ+TNF-α>IL-4) associated with increased heart inflammation and no beneficial effect on parasite control. Further, G-CSF controlled T. cruzi-induced extracellular-matrix alterations of collagens (Col I and Col llI), hydroxyproline, and glycosaminoglycan contents and promoted compensatory cardiac remodeling; however, these responses were not sufficient to control T. cruzi-induced cardiomyocyte atrophy. Benznidazole treatment prior to G-CSF resulted in the control of parasitism and parasite-induced inflammation, and subsequently, G-CSF was effective in executing the tissue repair, as evidenced by extracellular-matrix homeostasis and normalization of cardiomyocyte size in chagasic hearts. CONCLUSIONS: G-CSF treatment after T. cruzi infection enhanced migration and homing of BMSC, some of which differentiated to cardiomyocytes. Yet, G-CSF promoted a mixed (Treg>Th1>Th2) immune response that contributed to persistent inflammation and limited improvement in cardiac homeostasis. Combinatorial therapy (BZ → G-CSF) was beneficial in arresting inflammatory processes and tissue damage in chagasic hearts.
BACKGROUND: The hallmark of Trypanosoma cruzi infection is cardiomyopathy that leads to end-stage heart failure. We investigated whether G-CSF, known to induce heart tissue repair by bone marrow stem cell mobilization, ameliorates T. cruzi-induced myocarditis. METHODS AND RESULTS: T. cruzi-infected C3H/He mice were treated with G-CSF and monitored for parasite burden, BMSC mobilization, cytokine profile and cardiac remodeling. G-CSF increased the expression of CXCR4, CD34, and c-Kit, indicating mobilization and migration of BMSC, some of which differentiated to cardiomyocytes as evidenced by increased levels of GATA4(+)/MEF2C(+) cells and desmin expression in chagasic hearts. G-CSF enhanced a mixed cytokine response (IL-10+TGF-β>IFN-γ+TNF-α>IL-4) associated with increased heart inflammation and no beneficial effect on parasite control. Further, G-CSF controlled T. cruzi-induced extracellular-matrix alterations of collagens (Col I and Col llI), hydroxyproline, and glycosaminoglycan contents and promoted compensatory cardiac remodeling; however, these responses were not sufficient to control T. cruzi-induced cardiomyocyte atrophy. Benznidazole treatment prior to G-CSF resulted in the control of parasitism and parasite-induced inflammation, and subsequently, G-CSF was effective in executing the tissue repair, as evidenced by extracellular-matrix homeostasis and normalization of cardiomyocyte size in chagasic hearts. CONCLUSIONS:G-CSF treatment after T. cruzi infection enhanced migration and homing of BMSC, some of which differentiated to cardiomyocytes. Yet, G-CSF promoted a mixed (Treg>Th1>Th2) immune response that contributed to persistent inflammation and limited improvement in cardiac homeostasis. Combinatorial therapy (BZ → G-CSF) was beneficial in arresting inflammatory processes and tissue damage in chagasic hearts.
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