Volume 1 Issue 10, October 2022

Late fetal liver hematopoiesis was thought to primarily rely on hematopoietic stem cells (HSCs). Using new genetic-tracing tools, a study shows that EVI1-positive HSCs mainly undergo expansion in the fetal liver, while differentiated blood cell production depends on HSC-independent intermediate hematopoietic progenitors.

Mutations in Kir2.1 resulting in defects in trafficking to the cardiomyocyte sarcolemma promote arrhythmia in Anderson–Tawil syndrome. Macias and colleagues provide a dual mechanism underlying cardiac arrhythmia that involves chaperoning of voltage-gated Na⁺ channels and a unique population of intracellular Kir2.1 channels that regulate Ca²⁺ cycling at the sarcoplasmic reticulum.

A recent study by the GIGASTROKE consortium combines genetic discovery, fine-mapping and proteomic data to identify causal genes and variants related to disease. Results reveal known and new targets for prevention or treatment of stroke, and highlight the importance of genomics for drug discovery and development.

We explored age-dependent patterns in sex differences for a wide range of cardiometabolic disease risk factors and observed widespread and divergent patterns for different risk-factor groups. These findings highlight the importance of taking both age and sex into account when assessing a person’s risk of developing cardiometabolic disease.

Little is known about the maintenance of endothelial cell fate in adults. We show that deletion of Erg and Fli1 in endothelial cells of adult mice causes loss of endothelial cell fate and vascular collapse. Overexpression of ERG and FLI1 in non-vascular cells activates an endothelial cell program, confirming their regulation of endothelial cell identity.

Gomez-Salinero, Itkin et al. demonstrate the cooperative role of two ETS transcriptor factors, ERG and Fli1, in the active maintenance of endothelial cell homeostatic function. Loss of these two genes in adult mice leads to multi-organ failure, hyperinflammation, systemic thrombosis and death. In vitro, expression of both ERG and FLI1 induces human adult non-vascular mesenchymal stromal cells to acquire endothelial-like properties. In humans, several cardiovascular disorders and inflammatory-related diseases are linked to mutations in both genes.

Macias et al. generated a mouse model recapitulating the electrophysiological features of Andersen–Tawil syndrome type 1 (ATS1), a disease associated with life-threatening arrhythmias, via AAV-mediated in vivo expression of trafficking-deficient mutant Kir2.1^Δ314-315 channel. The authors identify functional Kir2.1 receptors in sarcoplasmic reticulum (SR) microdomains and report that the ATS1 arrhythmogenic phenotype is due to the dysfunction of Kir2.1 receptors both in the sarcolemma and in the SR domains.

Rodrigues et al. show that estrogen levels regulate bone endothelial cell (BEC) physiology. Low levels of estrogens impair fatty acid metabolism in BECs and lipolysis of adipocytes and cause accumulation of lipid peroxides (LPOs), leading to vascular aging. Inhibition of LPO generation significantly improved bone health in adult mice.

In a combined computational and multi-center clinical study to investigate the effects of adipose fat tissue infiltration on ventricular arrhythmias, Sung et al. show that infiltrating adipose tissue, as opposed to scar, is the main cause of infarcted-related ventricular arrhythmias by slowing cardiac conduction in critical sites.

Mantri et al. used spatial transcriptomics and scRNA-seq combined with smFISH to characterize the pathogenesis of reovirus-induced myocarditis in neonatal mice. They report a key role for endothelial cells in modulating the inflammatory response to the virus and a role for cytotoxic T-cell-induced pyroptosis in the cardiac pathology.