Cardiac Explant-Derived Cells Are Regulated by Notch-Modulated Mesenchymal Transition

Progenitor cell therapy is emerging as a novel treatment for heart failure. However the molecular mechanisms regulating the generation of cardiac progenitor cells is not fully understood. We hypothesized that cardiac progenitor cells are generated from cardiac explant via a process similar to epithelial to mesenchymal transition (EMT).Explant-derived cells were generated from partially digested atrial tissue. After 21 days in culture, c-Kit+ cells were isolated from cell outgrowth. The majority of explant-originated c-Kit+ cells expressed the epicardial marker Wt1. Cardiac cell outgrowth exhibits a temporal up-regulation of EMT-markers. Notch stimulation augmented, while Notch inhibition suppressed, mesenchymal transition in both c-Kit+ and c-Kit- cells. In c-Kit+ cells, Notch stimulation reduced, while Notch inhibition up-regulated pluripotency marker expressions such as Nanog and Sox2. Notch induction was associated with degradation of β-catenin in c-Kit- cells. In contrast, Notch inhibition resulted in β-catenin accumulation, acquisition of epitheloid morphology, and up-regulation of Wnt target genes in c-Kit- cells.Our study suggests that Notch-mediated reversible EMT process is a mechanism that regulates explant-derived c-Kit+ and c-Kit- cells

Endothelial to Mesenchymal Transition in Cardiovascular Disease: Key Mechanisms and Clinical Translation Opportunities

Endothelial to mesenchymal transition (EndMT) is a process whereby an endothelial cell undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell (e.g., myofibroblast, smooth muscle cell). EndMT plays a fundamental role during development, and mounting evidence indicates that EndMT is involved in adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis. Therefore, the targeting of EndMT may hold therapeutic promise for treating CVD. However, the field faces a number of challenges, including the lack of a precise functional and molecular definition, a lack of understanding of the causative pathological role of EndMT in CVDs (versus being a "bystander-phenomenon"), and a lack of robust human data corroborating the extent and causality of EndMT in adult CVDs. Here, we review this emerging but exciting field, and propose a framework for its systematic advancement at the molecular and translational levels. (J Am Coll Cardiol 2019; 73: 190-209) (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Continuous intra-gastral monitoring of intra-abdominal pressure in critically ill children: a validation study

Background!#!In critically ill children, detection of intra-abdominal hypertension (IAH > 10 mmHg) and abdominal compartment syndrome (ACS = IAH + organ dysfunction) is paramount and usually monitored through intra-vesical pressures (IVP) as current standard. IVP, however, carries important disadvantages, being time-consuming, discontinuous, with infection risk through observer-dependent manipulation, and ill-defined for catheter sizes. Therefore, we sought to validate air-capsule-based measurement of intra-gastric pressure (ACM-IGP).!##!Methods!#!We prospectively compared ACM-IGP with IVP both in vivo and in vitro (water column), according to Abdominal-Compartment-Society validation criteria. We controlled for patient age, admission diagnosis, gastric filling/propulsive medication, respiratory status, sedation levels and transurethral catheters, all influencing intra-abdominal pressure (IAP).!##!Results!#!In tertiary care PICU setting, finally, n = 97 children were enrolled (median age, 1.3 years [range 0 days-17 years], LOS-PICU 8.0 [1-332] days, PRISM-III-Score 13 [0-35]). In n = 2.770 measurements pairs, median IAP was 6.7 [0.9-23.0] mmHg, n = 38 (39%) children suffered from IAH > 10 mmHg, n = 4 from ACS. In vitro against water column, ACM-IGP correlated perfectly (r!##!Conclusions!#!In a large PICU population with high IAH prevalence, ACM-IGP agreed favourably with IVP. More widespread usage of ACM-IGP may improve detection rates of ACS in critically ill children. Trial registration WHO-ICTRP-No. DRKS00006556 (German Clinical Trial Register). Registered 12th September 2014, URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00006556

PRC2 directly methylates GATA4 and represses its transcriptional activity

The Polycomb-repressive complex 2 (PRC2) is a key factor in gene silencing. PRC2 represses gene transcription via methylation of its well-established target, histone H3K27. Pu and colleagues now demonstrate that PRC2 also has the ability to methylate nonhistone targets. The PRC2 subunit Ezh2 is found to bind and methylate the cardiac transcription factor GATA4, thereby interfering with its transcriptional activity and affecting heart development. This study thus uncovers a novel aspect of PRC2 activity in gene expression regulation

Pi3kcb Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival

Looking south from the Lily Pond to the arcade connecting the Casa de Balboa, left and the House of Hospitality on the right; Placed in reserve in 1835 (by the then Mexican government of Alta California), the park's site is one of the oldest in the United States dedicated to public recreational use (1868). The park hosted the 1915-1916 Panama-California Exposition and 1935-1936 California Pacific International Exposition, both of which left architectural landmarks. The park and its historic Exposition buildings were declared a National Historic Landmark District and also placed on the National Register in 1977. After 1962, the only 1915 Exposition buildings on El Prado were the California Building and its annexes, the House of Charm, the House of Hospitality, the Botanical Building, the Electric Building (rebuilt as Casa de Balboa in 1981) and the Food and Beverage Building (rebuilt as Casa del Prado, 1971). In addition to open space areas, natural vegetation green belts, gardens and walking paths, the park contains museums, several theaters, and the world-famous San Diego Zoo. Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 7/22/2013