RESUMO
Therapies based on transplantation of mesenchymal stromal cells (MSC) hold promise for the management of inflammatory disorders. In chronic Chagas disease cardiomyopathy (CCC), caused by chronic infection with Trypanosoma cruzi, the exacerbated immune response plays a critical pathophysiological role and can be modulated by MSC. Here, we investigated the role of galectin-3 (Gal-3), a beta-galactoside-binding lectin with several actions on immune responses and repair process, on the immunomodulatory potential of MSC. Gal-3 knockdown in MSC did not affect the immunophenotype or differentiation potential. However, Gal-3 knockdown MSC showed decreased proliferation, survival, and migration. Additionally, when injected intraperitoneally into mice with CCC, Gal-3 knockdown MSC showed impaired migration in vivo. Transplantation of control MSC into mice with CCC caused a suppression of cardiac inflammation and fibrosis, reducing expression levels of CD45, TNFα, IL-1ß, IL-6, IFNγ, and type I collagen. In contrast, Gal-3 knockdown MSC were unable to suppress the immune response or collagen synthesis in the hearts of mice with CCC. Finally, infection with T. cruzi demonstrated parasite survival in wild-type but not in Gal-3 knockdown MSC. These findings demonstrate that Gal-3 plays a critical role in MSC survival, proliferation, migration, and therapeutic potential in CCC.
RESUMO
Nos últimos anos estudos têm demonstrado a participação de citocinas e fatores de proliferação e diferenciação na regeneração do miocárdio em condições de agressão. Os fatores que inf1uenciam a regeneração do miocárdio na fase aguda da infecção por T. cruzi na qual ocorre um processo massivo de destruição do miocárdio. ainda são desconhecidos. Neste trabalho foi investigada a expressão dos genes de IIGF. IGF-l, VEGF e TNF-(x no coração de camundongos durante o curso da infecção aguda por T. Cruzi. Fragmentos de corações de camundongos C57Bl/6 infectados com cepa Colombiana de T. Cruzi. sacrificados com 15, 25, 30, 40 e 60 dias pós-infecção. foram analisados pela técnica de PCR em tempo real. A expressão dos genes de HGF. IGF-I. VEGF e TNF-a no coração foi avaliada e correlacionada ao grau de inflamação. fibrose e parasitemia nos tempos de infecção analisados. Foi observado um aumento significativo na expressão dos genes de TNF-a e IGF-l durante toda a fase aguda da infecção. enquanto que a expressão de HGF apresentou-se diminuída. Já a expressão do gene de VEGF não foi significativamente alterada no decorrer da infecção. As expressões dos genes de HGF. IGF-l e TNF-a apresentaram uma correlação negativa com a parasitemia e a inf1amação. Estes resultados indicam que o miocárdio produz vários mediadores solúveis em resposta à infecção por T. cruzi. que podem ter uma participação tanto nos mecanismos de lesão. como o TNF-a. como na recuperaçào da lesão tecidual promovida pela infecção por T cruzi. como é o caso do IGF-l. Outros estudos devem ser realizados no sentido de melhor entender o papel destes mediadores produzidos localmente ou trazidos pela circulação no processo de reparo do miocárdio pela infecção por T. cruzi.
Studies carried out in the past few years have demonstrated the participation of cytokines and growth factors related to cell proliferation and differentiation in the regeneration of the myocardium after injury. The factors involved in the regeneration of the myocardium duringthe acute phase of T. cruzi infection, when a process of massive destruction of themyocardium occurs, are not known. In this work we investigated the gene expression of HGF, IGF-1, VEGF e TNF-á in the hearts of mice during the acute infection by T. cruzi. Heart fragments of C57Bl/6 mice infected by Colombian strain T. cruzi were obtained 15, 25 30, 40e 60 days after infection and analyzed by real time PCR. The gene expression of HGF, IGF-1, VEGF, and TNF-á in the heart was evaluated and correlated to the degree of inflammation, fibrosis and parasitemia at the time points analyzed. A significant increase in TNF-á and IGF-1 gene expression was observed during the acute phase of infection, whereas theexpression of HGF was decreased. The expression of VEGF gene was not significantly altered during infection. The expression of HGF, IGF-1, and TNF-á genes showed a negative correlation with parasitemia and inflammation. The results indicate the miocardium as a source of soluble mediators, in response to T. cruzi infection, which may participate both inthe mechanisms of lesion induction, in the case of TNF-á, as well as in the repair of tissue lesions promoted by T. cruzi infection, such as IGF-1. Additional studies should be carried out in order to understand the role of these mediators produced locally or brought by thecirculation in the process of lesion repair in the miocardium during T. cruzi infection.
