Single-cell transcriptome analyses reveal novel targets modulating cardiac neovascularization by resident endothelial cells following myocardial infarction.

AIMS: A better understanding of the pathways that regulate regeneration of the coronary vasculature is of fundamental importance for the advancement of strategies to treat patients with heart disease. Here, we aimed to investigate the origin and clonal dynamics of endothelial cells (ECs) associated with neovascularization in the adult mouse heart following myocardial infarction (MI). Furthermore, we sought to define murine cardiac endothelial heterogeneity and to characterize the transcriptional profiles of pro-angiogenic resident ECs in the adult mouse heart, at single-cell resolution. METHODS AND RESULTS: An EC-specific multispectral lineage-tracing mouse (Pdgfb-iCreERT2-R26R-Brainbow2.1) was used to demonstrate that structural integrity of adult cardiac endothelium following MI was maintained through clonal proliferation by resident ECs in the infarct border region, without significant contributions from bone marrow cells or endothelial-to-mesenchymal transition. Ten transcriptionally discrete heterogeneous EC states, as well as the pathways through which each endothelial state is likely to enhance neovasculogenesis and tissue regeneration following ischaemic injury were defined. Plasmalemma vesicle-associated protein (Plvap) was selected for further study, which showed an endothelial-specific and increased expression in both the ischaemic mouse and human heart, and played a direct role in regulating human endothelial proliferation in vitro. CONCLUSION: We present a single-cell gene expression atlas of cardiac specific resident ECs, and the transcriptional hierarchy underpinning endogenous vascular repair following MI. These data provide a rich resource that could assist in the development of new therapeutic interventions to augment endogenous myocardial perfusion and enhance regeneration in the injured heart

Macrophages trigger cardiomyocyte proliferation by increasing epicardial vegfaa expression during larval zebrafish heart regeneration

Cardiac injury leads to the loss of cardiomyocytes, which are rapidly replaced by the proliferation of the surviving cells in zebrafish, but not in mammals. In both the regenerative zebrafish and non-regenerative mammals, cardiac injury induces a sustained macrophage response. Macrophages are required for cardiomyocyte proliferation during zebrafish cardiac regeneration, but the mechanisms whereby macrophages facilitate this crucial process are fundamentally unknown. Using heartbeat-synchronized live imaging, RNA sequencing, and macrophage-null genotypes in the larval zebrafish cardiac injury model, we characterize macrophage function and reveal that these cells activate the epicardium, inducing cardiomyocyte proliferation. Mechanistically, macrophages are specifically recruited to the epicardial-myocardial niche, triggering the expansion of the epicardium, which upregulates vegfaa expression to induce cardiomyocyte proliferation. Our data suggest that epicardial Vegfaa augments a developmental cardiac growth pathway via increased endocardial notch signaling. The identification of this macrophage-dependent mechanism of cardiac regeneration highlights immunomodulation as a potential strategy for enhancing mammalian cardiac repair

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

Key Points Aberrations in genome maintenance and DNA repair genes including POT1 occur at a high frequency in Sézary syndrome. Candidate driver genes and affected pathways in Sézary syndrome show extensive heterogeneity but overlap with other mature T-cell lymphomas.</jats:p

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

© 2014 The Author 2014. Published by Oxford University Press. All rights reserved. In the present contribution, we address the idea that income inequality can 'get under the skin' and worsen the symptoms of depression. We investigate whether this effect can be explained by country differences in the average coping resources citizens have at their disposal, as well as the average extent to which they engage in social comparisons. In addition, we examine whether coping resources can protect individuals from the detrimental effect of inequality and whether the effect of inequality varies according to socio-economic (SES) positions. We use multilevel techniques on a sample of 43,824 respondents collected by the European Social Survey (ESS) 2006/2007 in 23 European countries and find that individuals in countries with greater income inequalities report more depressive symptoms. Although social comparisons are associated with more depressive symptoms, they do not explain the effect of inequality and neither do coping resources. However, we do find that coping resources can protect against the stress of living in a society with high income inequality. Our results provide some support for the idea that inequality is most corrosive to the mental health of the people in the middle of the income hierarchy.status: publishe