Mesenchymal Stem Cells Promote the Resolution of Cardiac Inflammation After Ischemia Reperfusion Via Enhancing Efferocytosis of Neutrophils.
- 作者列表："Zhang Z","Tian H","Yang C","Liu J","Zhang H","Wang J","Hu S","Sun Z","He K","Chen G
:Background Neutrophils play a major role in inflammation after myocardial ischemia-reperfusion (I/R) injury. The effects of mesenchymal stem cells (MSCs) on neutrophils in I/R are complex and not fully understood. This study was designed to investigate the effects and mechanism of MSCs on alleviating myocardial I/R injury in rats. Methods and Results MSCs induced M2 macrophages polarization in vitro and enhanced macrophage efferocytosis of apoptotic neutrophils, measured by fluorescence-activated cell sorting analysis and immunofluorescence staining. Rats myocardial I/R were induced by transient ligation of left anterior descending coronary. Adipose-derived MSCs or vehicle were infused at initiation (immediate after reperfusion) or peak of inflammation (24 hours after I/R). Hematoxylin and eosin, 2,3,5-triphenyltetrazolium chloride/Evans Blue staining and immunofluorescence staining were applied within 72 hours after cell infusion. Cardiac function was assessed by echocardiography and left cardiac catheterization analysis at 28 days post-operation. MSCs infused immediately and 24 hours later both markedly ameliorated myocardial I/R injury, and immediate infusion had more significant outcome. These improvements were associated with neutrophils infiltration, measured by fluorescence-activated cell sorting analysis and immunofluorescence staining. When infused immediately, MSCs did not significantly change neutrophil number at 24 hours but CD11b expression was significantly higher. When infused at 24 hours, MSCs markedly decreased neutrophil number by enhanced M2 macrophage infiltration and macrophage efferocytosis of neutrophils within 72 hours. Conclusions Efferocytosis is pivotal to relieve neutrophil-mediated I/R injury and initial the immune response for healing. MSCs infusion improves cardiac function in rats after myocardial I/R via the possible mechanism of enhancing M2 macrophages-induced efferocytosis of apoptotic neutrophils.
背景: 中性粒细胞在心肌缺血再灌注 (I/R) 损伤后的炎症反应中起主要作用。间充质干细胞 (MSCs) 在 I/R 中对中性粒细胞的影响是复杂的，尚不完全清楚。本研究旨在探讨 MSCs 减轻大鼠心肌 I/R 损伤的作用及机制。方法和结果 MSCs 在体外诱导 M2 巨噬细胞极化，通过荧光激活细胞分选分析和免疫荧光染色检测，增强凋亡中性粒细胞的巨噬细胞胞吐。通过短暂结扎左冠状动脉前降支诱导大鼠心肌 I/R。在开始 (再灌注后立即) 或炎症高峰 (I/R 后 24 小时) 输注脂肪来源的 MSCs 或溶剂。细胞输注后 72 h 内应用苏木精伊红、 2,3 、氯化 5-三苯基四氮唑/伊文思蓝染色和免疫荧光染色。术后 28 天通过超声心动图和左心导管分析评估心功能。即刻和 24 h 后输注的 MSCs 均明显改善心肌 I/R 损伤，即刻输注的结果更显著。这些改善与中性粒细胞浸润有关，通过荧光激活细胞分选分析和免疫荧光染色测定。当立即输注时，MSCs 在 24 h 时中性粒细胞数量无明显变化，但 CD11b 表达明显增高。MSCs 在 24 小时内通过增强 M2 巨噬细胞浸润和巨噬细胞增多作用，使中性粒细胞数量明显减少。结论胞吐对缓解中性粒细胞介导的 I/R 损伤和启动愈合的免疫反应至关重要。MSCs 输注通过增强 M2 巨噬细胞诱导的凋亡中性粒细胞逸出作用的可能机制改善心肌 I/R 后大鼠的心功能。
METHODS:BACKGROUND:Preterm birth is a risk factor for elevated blood pressure in childhood and the development of hypertension and cardiometabolic disease in adulthood; however, mechanisms for the development of both are poorly understood. Rapid weight gain early in childhood may serve as a driver directly and indirectly through cortisol levels found to be elevated in early childhood in individuals born preterm. OBJECTIVES:The objective of this pilot study was to examine the effect sizes of the relationships between weight gain and blood pressure in toddlers born very preterm. A secondary aim was to note any mediating effect of cortisol on the relationships between weight gain and blood pressure. METHODS:A cross-sectional design with a convenience sample of 36 toddlers who were born very preterm was used to examine the relationships between postnatal weight gain, cortisol, and blood pressure at follow-up. RESULTS:Many of the participants experienced rapid weight gain in the first 12 months of life. Mean systolic and diastolic readings were 94 and 56.6, respectively. Diastolic blood pressure readings were obtained from 23 participants and the majority were elevated. Weight gain was associated with diastolic blood pressure with a medium effect size. A mediating role with cortisol was not supported.Although findings need to be validated in a larger sample, the blood pressure elevations in this sample were alarming. If readings continue to amplify as these children age, the fact that elevations are already present during the toddler period could indicate more significant cardiovascular disease in adulthood for this population. Rapid weight gain in early life may be a driver for elevated blood pressure even during early childhood in individuals born preterm.
METHODS:This article presents a case series of n = 21 models of fetal cardiovascular anatomies obtained from post mortem microfocus computed tomography (micro-CT) data. The case series includes a broad range of diagnoses (e.g., tetralogy of Fallot, hypoplastic left heart syndrome, dextrocardia, double outlet right ventricle, atrio-ventricular septal defect) and cases also had a range of associated extra-cardiac malformations (e.g., VACTERL syndrome, central nervous system anomalies, renal anomalies). All cases were successfully reconstructed from the microfocus computed tomography data, demonstrating the feasibility of the technique and of the protocols, including in-house printing with a desktop 3D printer (Form2, Formlabs). All models were printed in 1:1 scale as well as with the 5-fold magnification, to provide insight into the intra-cardiac structures. Possible uses of the models include education and training.
METHODS:Abstract Background Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently. De novo variants are estimated to contribute to approximately 8% of sporadic CHD. Methods CHD is genetically heterogeneous, making pathway enrichment analysis an effective approach to explore and statistically validate CHD-associated genes. In this study, we performed novel gene and pathway enrichment analyses of high-impact de novo variants in the recently published whole-exome sequencing (WES) data generated from a cohort of CHD 2645 parent-offspring trios to identify new CHD-causing candidate genes and mutations. We performed rigorous variant- and gene-level filtrations to identify potentially damaging variants, followed by enrichment analyses and gene prioritization. Results Our analyses revealed 23 novel genes that are likely to cause CHD, including HSP90AA1, ROCK2, IQGAP1, and CHD4, and sharing biological functions, pathways, molecular interactions, and properties with known CHD-causing genes. Conclusions Ultimately, these findings suggest novel genes that are likely to be contributing to CHD pathogenesis.