Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with T. cruzi and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFβ1) and T. cruzi stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of T. cruzi-infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC.

Background: Coronavirus disease 2019 (COVID-19) associated- severe acute respiratory distress syndrome (ARDS) patients may require prolonged mechanical ventilation, thus resulting in lung fibrosis and high fatality rates. Several therapies have been developed in patients with pneumonia requiring oxygen therapy as well as during the early course of invasive mechanical ventilation. Mesenchymal stromal cells (MSCs) may have a role in controlling the hyperinflammatory response seen in such cases and prevent aggravation or increase/accelerate recovery. While MSC-based therapies have been studied mostly in patients that did not require invasive ventilation or during the first hours of tracheal intubation, to date the potential of MSC therapy to treat advanced-stage of severe/critical COVID-19 cases has not been extensively studied. Methods: This is a case report of a 30-year-old male patient who presented progressive clinical deterioration of COVID-19 in ICU after 21-day admission and 14 days with invasive mechanical ventilation. The first symptom onset was 35 days before MSC therapy. The patient was treated with allogenic human umbilical cord-derived MSCs [5 x 107 (2 doses 2 days interval)].Results: No serious adverse events attributed to MSC administration were observed during and after the procedure. Oxygenation (PaO2/FiO2 ratio) and the need for vasoactive drugs improved. Chest CT scan imaging, which showed signs of bilateral and peripheral ground-glass, consolidation as well as fibrosis, improved significantly during the time course of the disease. Patient was discharged 13 days after cell therapy. Cytokine analysis demonstrated modulation of different mediators accompanied by modulation of different cell populations in peripheral blood, including a reduction in inflammatory monocytes, increased frequency of patrolling monocytes, CD4+ lymphocytes and type 2 classical dendritic cells (cDC2). Conclusion: This study described for the first time the effects of MSC therapy in a patient at late stage COVID-19 associated severe lung injury and fibrosis. Therefore, further clinical trials should be design assessing the efficacy of MSC therapy in ARDS patients undergoing prolonged mechanical ventilation due to COVID-19.