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Mesothelial and epicardial cells give rise to various types of mesenchymal cells via epithelial (mesothelial)‐to‐mesenchymal transition during development. However, the genes controlling the differentiation and diversification of mesothelial/epicardial cells remain unclear. Here, we examined Wnt2b expression in the embryonic mesothelium and epicardium and performed lineage tracing of Wnt2b‐expressing cells by using novel Wnt2b‐2A‐CreERT2 knock‐in and LacZ‐reporter mice. Wnt2b was expressed in mesothelial cells covering visceral organs, but the expression was restricted in their subpopulations. Wnt2b‐expressing cells labeled at embryonic day (E) 10.5 were distributed to the mesothelium and mesenchyme in the lungs, abdominal wall, stomach, and spleen in Wnt2b2A‐CreERT2/+;R26RLacZ/+ mice at E13.0. Wnt2b was initially expressed in the proepicardial organ (PEO) at E9.5 and then in the epicardium after E10.0. Wnt2b‐expressing PEO cells labeled at E9.5 differentiated into a small fraction of cardiac fibroblasts and preferentially localized at the left side of the postnatal heart. LacZ+ epicardium‐derived cells labeled at E10.5 differentiated into a small fraction of fibroblasts and smooth muscle cells in the postnatal heart. Taken together, our results reveal novel subpopulations of PEO and mesothelial/epicardial cells that are distinguishable by Wnt2b expression and elucidate the unique contribution of Wnt2b‐expressing PEO and epicardial cells to the postnatal heart. [ABSTRACT FROM AUTHOR]

Despite rapid advances in our understanding of adult stem-cell biology, the immunological attributes of somatic stem-cell niches have remained largely unexplored. We hypothesized that the HSPC niche within the bone [...], Stem cells reside in a specialized regulatory microenvironment or niche (1,2), where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity (1-3). The niche may also protect stem cells from environmental insults (3) including cytotoxic chemotherapy and perhaps pathogenic immunity (4). The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression (4). We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche (1,2,5-7) in the bone marrow, a site where immune reactivity exists (8,9). We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T ([T.sub.reg]) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with [T.sub.reg] cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. [T.sub.reg] cells seem to participate in creating a localized zone where HSPCs reside and where [T.sub.reg] cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.

Significance: Magnetic resonance imaging (MRI) with hyperpolarized (HP) 13C-labeled redox-sensitive metabolic tracers can provide noninvasive functional imaging biomarkers, reflecting tissue redox state, oxidative stress, and inflammation, among others. The capability to use endogenous metabolites as 13C-enriched imaging tracers without structural modification makes HP 13C MRI a promising tool to evaluate redox state in patients with various diseases. Recent Advances: Recent studies have demonstrated the feasibility of in vivo metabolic imaging of 13C-labeled tracers polarized by parahydrogen-induced polarization techniques, which offer a cost-effective alternative to the more widely used dissolution dynamic nuclear polarization-based hyperpolarizers. Critical Issues: Although the fluxes of many metabolic pathways reflect the change in tissue redox state, they are not functionally specific. In the present review, we summarize recent challenges in the development of specific 13C metabolic tracers for biomarkers of redox state, including that for detecting reactive oxygen species. Future Directions: Applications of HP 13C metabolic MRI to evaluate redox state have only just begun to be investigated. The possibility to gain a comprehensive understanding of the correlations between tissue redox potential and metabolism under different pathological conditions by using HP 13C MRI is promoting its interest in the clinical arena, along with its noninvasive biomarkers to evaluate the extent of disease and treatment response. [ABSTRACT FROM AUTHOR]

Background: Variants in the LZTR1 (leucine‐zipper‐like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking. Methods: By CRISPR‐Cas9 genome editing, we generated lztr1‐mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome. Results: A frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss‐of‐function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome‐associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue. Conclusion: Our novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss‐of‐function mechanism of disease‐causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow‐up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology. [ABSTRACT FROM AUTHOR]

The aim of this study was to address 7-year clinical outcomes and impact of prolonged dual antiplatelet therapy (DAPT) after coronary stenting in hemodialysis patients. Our study included 123 consecutive hemodialysis patients who had undergone percutaneous coronary intervention with a drug-eluting stent (DES) or bare-metal stent (BMS) (DES: 64, BMS: 59) in our institution. We compared long-term clinical outcomes following DES with BMS implantation as well as clinical outcomes in patients on DAPT for ≥1 year (DAPT on group, 89) with those on DAPT for <1 year (DAPT off group, 34). We evaluated bleeding events and major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, target vessel revascularization, and stent thrombosis. At 1 year after stenting, the incidence of MACE was significantly lower in the DES group than in the BMS group (DES versus BMS: 33.2 versus 51.8%; p = 0.045). However, this advantage of DES disappeared by the 7th year (DES versus BMS: 66.0 versus 70.0%; p = 0.42). The cumulative incidence of MACE beyond 1 year was significantly higher in the DAPT on group than in the DAPT off group (DAPT on versus DAPT off: 51.3 versus 18.5%; p = 0.047). The bleeding events in the DAPT on group were 5.1 times greater than in the DAPT off group (DAPT on versus DAPT off: 16.4 versus 3.2%; p = 0.06). Use of DES and prolonged DAPT did not improve 7-year clinical outcomes in hemodialysis patients with coronary artery disease. [ABSTRACT FROM AUTHOR]

Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30?days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (Treg) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with Treg cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. Treg cells seem to participate in creating a localized zone where HSPCs reside and where Treg cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack. [ABSTRACT FROM AUTHOR]

Tight blood pressure control over a long period is important to prevent end-organ damage to the brain, heart, and kidneys, and to avoid the complications of hypertension. Control requires an accurate evaluation of treatment through an appropriate monitoring of home blood pressure. In this study, we evaluated a method of home blood pressure monitoring, in which we propose a home blood pressure distribution diagram to evaluate the effectiveness of anti-hypertensive therapy. 1 ) In home blood pressure measurements, the first reading was high, while the second and third readings were essentially similar and thus stable. 2 ) Home blood pressure showed great daily variations, thus necessitating the use of the mean blood pressure over a fixed period, and not the individual blood pressure readings. The mean (morning, mid-day, and evening) over a one-week period was unstable, while the readings were stable over a three-week period. 3 ) The diagrams showing the distribution of home blood pressure measurements obtained in the morning and at night over a long period allowed the degree of early morning hypertension and the effectiveness of long-term blood pressure control to be assessed, and thus were useful for selecting anti-hypertensive agents. 4 ) In elderly patients, a mid-day systolic pressure of 100 mmHg or less (particularly 90 mmHg or less) resulted in the onset of symptoms of excessive hypotensive effects, such as lightheadedness and fainting, which affected ADL and QOL. 5 ) Because of great daily variations, it is difficult to achieve the blood pressure target of 130/80 mmHg or less in patients with hypertension associated with diabetes mellitus or renal insufficiency. 6 ) The home blood pressure distribution diagram facilitated an understanding of the status of anti-hypertensive therapy by patients, and was useful for motivating patients to continue treatment.