Background: COVID-19 is a deadly pulmonary disease with peculiar characteristics, which include variable clinical course and thrombophilia. A thorough understanding of the pathological correlates of the disease is still missing. Methods: Here we report the systematic analysis of 41 consecutive post-mortem samples from individuals who died of COVID-19. Histological analysis is complemented by immunohistochemistry for cellular and viral antigens and the detection of viral genomes by in situ RNA hybridization. Findings: COVID-19 is characterized by extensive alveolar damage (41/41 of patients) and thrombosis of the lung micro-and macro-vasculature (29/41, 71%). Thrombi were in different stages of organization, consistent with their local origin. Pneumocytes and endothelial cells contained viral RNA even at the later stages of the disease. An additional feature was the common presence of a large number of dysmorphic pneumocytes, often forming syncytial elements (36/41, 87%). Despite occasional detection of virus-positive cells, no overt signs of viral infection were detected in other organs, which showed non-specific alterations. Interpretation: COVID-19 is a unique disease characterized by extensive lung thrombosis, long-term persistence of viral RNA in pneumocytes and endothelial cells, along with the presence of infected cell syncytia. Several of COVID-19 features might be consequent to the persistence of virus-infected cells for the duration of the disease.
Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction.
The crosstalk between endothelial cells and cardiomyocytes has emerged as a requisite for normal cardiac development, but also a key pathogenic player during the onset and progression of cardiac disease. Endothelial cells and cardiomyocytes are in close proximity and communicate through the secretion of paracrine signals, as well as through direct cell-to-cell contact. Here, we provide an overview of the endothelial cell-cardiomyocyte interactions controlling heart Serena Zacchigna and Mauro Giacca serve as Professors of Molecular Biology at the University of Trieste, Italy and Principle Investigators of the Cardiovascular Biology and Molecular Medicine laboratories of the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Trieste, Italy, respectively. Mauro Giacca also serves as the Director-General of the ICGEB. Andrea Colliva and Luca Braga are post-docs in the same laboratories. The main research interests of Serena Zacchigna focus around the mechanisms leading to new blood vessel formation in ischaemic muscles and hearts, whereas MauroGiacca is a leader in the field of cardiac regeneration, having particular interest in understanding why mammalian cardiomyocytes permanently exit from the cell cycle at birth and how this can be overcome therapeutically. The two laboratories have been extensively collaborating over the last few years to explore the intercellular crosstalk between cardiomyocytes and cardiac endothelial cells.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 2A. Colliva and others J Physiol 00.0 development and the main processes affecting the heart in normal and pathological conditions, including ischaemia, remodelling and metabolic dysfunction. We also discuss the possible role of these interactions in cardiac regeneration and encourage the further improvement of in vitro models able to reproduce the complex environment of the cardiac tissue, in order to better define the mechanisms by which endothelial cells and cardiomyocytes interact with a final aim of developing novel therapeutic opportunities.Abstract figure legend Cardiomyocytes (labelled in red by anti-α-actinin antibodies) and endothelial cells (labelled in green by anti-CD31 antibodies) crosstalk in multiple ways, including paracrine communication (dashed arrows) through either secreted molecules or vesicles (red circles), direct cell-cell contact (hinges) and autocrine signalling (curved arrows). This crosstalk plays an important role during embryonic development, normal post-natal life and several pathological conditions, thus representing a novel target for the treatment of cardiovascular disorders.
Sorting of mRNAs in neuronal dendrites relies upon inducible transport mechanisms whose molecular bases are poorly understood. We investigated here the mechanism of inducible dendritic targeting of rat brain-derived neurotrophic factor (BDNF) mRNAs as a paradigmatic example. BDNF encodes multiple mRNAs with either short or long 3′ UTR, both hypothesized to harbor inducible dendritic targeting signals. However, the mechanisms of sorting of the two 3′ UTR isoforms are controversial. We found that dendritic localization of BDNF mRNAs with short 3′ UTR was induced by depolarization and NT3 in vitro or by seizures in vivo and required CPEB-1, -2 and ELAV-2, -4. Dendritic targeting of long 3′ UTR was induced by activity or BDNF and required CPEB-1 and the relief of soma-retention signals mediated by ELAV-1, -3, -4, and FXR proteins. Thus, long and short 3′ UTRs, by using different sets of RNA-binding proteins provide a mechanism of selective targeting in response to different stimuli which may underlay distinct roles of BDNF variants in neuronal development and plasticity.
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