Abstract
Genetic modification of mesenchymal stem cells (MSCs) is a promising strategy to improve their therapeutic effects. Granulocyte-colony stimulating factor (G-CSF) is a growth factor widely used in the clinical practice with known regenerative and immunomodulatory actions, including the mobilization of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Here we evaluated the therapeutic potential of MSCs overexpressing G-CSF (MSC_G-CSF) in a model of inflammatory cardiomyopathy due to chronic Chagas disease. C57BL/6 mice were treated with wild-type MSCs, MSC_G-CSF, or vehicle (saline) 6 months after infection with Trypanosoma cruzi. Transplantation of MSC_G-CSF caused an increase in the number of circulating leukocytes compared to wild-type MSCs. Moreover, G-CSF overexpression caused an increase in migration capacity of MSCs to the hearts of infected mice. Transplantation of either MSCs or MSC_G-CSF improved exercise capacity, when compared to saline-treated chagasic mice. MSC_G-CSF mice, however, were more potent than MSCs in reducing the number of infiltrating leukocytes and fibrosis in the heart. Similarly, MSC_G-CSF-treated mice presented significantly lower levels of inflammatory mediators, such as IFNγ, TNFα, and Tbet, with increased IL-10 production. A marked increase in the percentage of Tregs and MDSCs in the hearts of infected mice was seen after administration of MSC_G-CSF, but not MSCs. Moreover, Tregs were positive for IL-10 in the hearts of T. cruzi-infected mice. In vitro analysis showed that recombinant hG-CSF and conditioned medium of MSC_G-CSF, but not wild-type MSCs, induce chemoattraction of MDSCs in a transwell assay. Finally, MDSCs purified from hearts of MSC_G-CSF transplanted mice inhibited the proliferation of activated splenocytes in a co-culture assay. Our results demonstrate that G-CSF overexpression by MSCs potentiates their immunomodulatory effects in our model of Chagas disease and suggest that mobilization of suppressor cell populations such as Tregs and MDSCs as a promising strategy for the treatment of chronic Chagas disease. Finally, our results reinforce the therapeutic potential of genetic modification of MSCs, aiming at increasing their paracrine actions.
Highlights
Mesenchymal stem cells (MSCs) are known to participate in tissue homeostasis and repair processes in different physiological and pathological settings [1]
Granulocyte-colony stimulating factor (G-CSF) has been described as a tumor-derived factor that recruits and expand myeloid-derived suppressor cells (MDSCs), which secrete cytokines involved in the induction of regulatory T cells (Tregs), contributing to the immunosuppressive tumor microenvironment [8]
Since G-CSF is known to induce the mobilization of immune regulatory cells [17], we evaluated the presence of MDSCs and Tregs in the hearts of T. cruzi-infected mice 30 days after the beginning of the cell therapy protocol
Summary
Mesenchymal stem cells (MSCs) are known to participate in tissue homeostasis and repair processes in different physiological and pathological settings [1]. Granulocyte-colony stimulating factor (G-CSF) has received significant attention in the regenerative medicine field due to well-known actions, especially regarding the mobilization of bone marrow-derived stem cells to the peripheral blood [6]. G-CSF has been described as a tumor-derived factor that recruits and expand myeloid-derived suppressor cells (MDSCs), which secrete cytokines involved in the induction of regulatory T cells (Tregs), contributing to the immunosuppressive tumor microenvironment [8]. These mechanisms of immune escape are being applied to potentiate immunomodulatory interventions to treat inflammatory diseases [9]
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