scholarly journals Selective and inducible targeting of CD11b+mononuclear phagocytes in the murine lung with hCD68-rtTA transgenic systems

2016 ◽  
Vol 311 (1) ◽  
pp. L87-L100 ◽  
Author(s):  
Alexandra L. McCubbrey ◽  
Lea Barthel ◽  
Kara J. Mould ◽  
Michael P. Mohning ◽  
Elizabeth F. Redente ◽  
...  
Keyword(s):  
Lineage Tracing ◽  
Mononuclear Phagocytes ◽  
Acute Lung Inflammation ◽  
Unique Role ◽  
Murine Lung ◽  
Disease States ◽  
Reporter Mice ◽  
Gfp Reporter ◽  
Low Levels

During homeostasis two distinct macrophage (Mø) populations inhabit the lungs: tissue Mø (often called interstitial Mø) and resident alveolar Mø (resAMø). During acute lung inflammation, monocytes from the circulation migrate to areas of injury where they mature into a third Mø population: recruited Mø. Resident AMø uniquely express low levels of CD11b and high levels of CD11c. In comparison, recruited Mø and tissue Mø express high levels of CD11b and low levels of CD11c. It is likely that these three Mø subpopulations play distinct roles in injury and disease states; however, tools with which to individually target or track these populations are lacking. Here we demonstrate the utility of an hCD68-rtTA transgenic system for specific, robust, and inducible targeting of CD11b+recruited Mø and tissue Mø in the murine lung with negligible activation in resAMø. Using hCD68rtTA-GFP reporter mice, we show both during homeostasis and inflammation that administration of doxycycline induces tet-On reporter expression in recruited Mø and tissue Mø but not in resident AMø. We further demonstrate how hCD68-rtTA can be effectively combined with tet-On Cre to target these same recMø and tissue Mø. Accordingly, the hCD68-rtTA system is a powerful new tool that can be used for lineage tracing, fate mapping, and gene deletion in a variety of murine models, thereby enabling sophisticated investigation of the unique role of these CD11b+Mø during lung heath and disease.

Abstract MP123: The Fate and Role of Pericytes in Repair and Remodeling of the Infarcted Heart

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Linda Alex ◽  
Ya Su ◽  
Nikolaos G Frangogiannis
Keyword(s):  
Lineage Tracing ◽  
Mrna Levels ◽  
Infarct Zone ◽  
Subsequent Formation ◽  
Mural Cells ◽  
Infarcted Heart ◽  
Reporter Mice ◽  
Ng2 Cells ◽  
Migratory Phenotype

Repair of the infarcted heart is dependent on inflammation-driven activation of myofibroblasts (MFs) and subsequent formation of a scar. Though pericytes have been implicated in injury-associated fibroblast activation in several organs, their potential role in cardiac repair and fibrosis has not been studied. We hypothesized that myocardial infarction (MI) may induce pericyte activation, contributing to repair through pericyte to MF conversion, secretion of fibrogenic mediators, or regulation of angiogenesis. In order to test the hypothesis, we generated pericyte/fibroblast reporter mice (NG2 DsRed ;PDGFRα GFP ). In normal myocardium, NG2 labeled peri-endothelial mural cells that coexpressed PDGFRβ, whereas PDGFRα identified interstitial cells with fibroblast characteristics. Pericytes and fibroblasts had distinct transcriptomic profiles: NG2+/PDGFRα- pericytes expressed αSMA and low amounts of extracellular matrix (ECM) genes, whereas PDGFRα+/NG2- fibroblasts synthesized collagens. Pericyte rarefaction was noted in the necrotic core 3 days after non-reperfused MI. 3-7 days post MI, expansion of the NG2+ population in the infarct zone was associated with emergence of non-mural NG2+/αSMA+ cells with MF characteristics. FACS-sorted NG2+/PDGFRα- cells from 7-day infarcts expressed higher levels of ColIα2 (7.2±1.0-fold) and ColIIIα1 (8.9±1.14-fold), when compared to NG2+/PDGFRα- cells from normal hearts. NG2+ cells had high mRNA levels of integrins α1, αV, β1, and β5, and of MMP14, reflecting an activated migratory phenotype. To examine whether expression of ECM genes by infarct pericytes is due to fibroblast conversion, we did lineage tracing studies using NG2CreER TM ;Rosa tdTomato mice bred with the PDGFRα GFP line for reliable fibroblast identification. 7 days post MI, 5.7%±1.04 of PDGFRα+ fibroblasts were derived from NG2+ cells. Also, αSMA staining showed that 10.49%±2.73 of infarct MFs were derived from NG2+ lineage. The majority of mural cells wrapping neovessels were derived from NG2+ cells, suggesting a role for resident pericytes in infarct angiogenesis. In conclusion, upon MI, pericytes become activated and contribute to repair by undergoing conversion to a subset of myofibroblasts and by coating infarct neovessels.

scholarly journals Targeting fibroblast CD248 attenuates CCL17-expressing macrophages and tissue fibrosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chen-Hsueh Pai ◽  
Shu-Rung Lin ◽  
Chia-Hao Liu ◽  
Szu-Yu Pan ◽  
Hao Hsu ◽  
...  
Keyword(s):  
Type I ◽  
Murine Models ◽  
Peritoneal Fibrosis ◽  
Tissue Fibrosis ◽  
Transmembrane Glycoprotein ◽  
Reporter Mice ◽  
Gfp Reporter ◽  
Galectin 3 ◽  
Activated Fibroblasts

Abstract The role of fibroblasts in tissue fibrosis has been extensively studied. Activated fibroblasts, namely myofibroblasts, produce pathological extracellular matrix. CD248, a type I transmembrane glycoprotein, is expressed in fibroblasts after birth. In human chronic kidney disease, upregulated CD248 in myofibroblasts is linked to poor renal survival. In this study, we demonstrated a novel interaction between CD248 and macrophages to be a key step in mediating tissue fibrosis. CD248 was upregulated in myofibroblasts in murine models of renal and peritoneal fibrosis. Cd248 knockout (Cd248–/–) could attenuate both renal and peritoneal fibrosis. By parabiosis of GFP reporter mice and Cd248–/– mice, we showed that attenuation of renal fibrosis was associated with a decrease of macrophage infiltration in Cd248–/– mice. Moreover, decrease of chemokine (C–C motif) ligand 17 and Ccl22 was found in macrophages isolated from the fibrotic kidneys of Cd248–/– mice. Because galectin-3-deficient macrophages showed decreased Ccl17 and Ccl22 in fibrotic kidneys, we further demonstrated that CD248 interacted specifically with galectin-3 of macrophages who then expressed CCL17 to activate collagen production in myofibroblasts. Mice with DNA vaccination targeting CD248 showed decreased fibrosis. We thus propose that CD248 targeting should be studied in the clinical tissue fibrosis setting.

Abstract 162: Resident Aortic Intimal Mononuclear Phagocytes (MNPs) in the Promotion of Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jesse W Williams ◽  
Ki-Wook Kim ◽  
Stoyan Ivanov ◽  
Slava Epelman ◽  
Kory Lavine ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cell Tracking ◽  
Lineage Tracing ◽  
Mononuclear Phagocytes ◽  
Gm Csf ◽  
Reporter Mice ◽  
En Face ◽  
A Cell ◽  
Functional Analyses ◽  
First Time

Atherosclerosis is an underlying cause of cardiovascular disease (CVD) and a leading cause of morbidity and mortality worldwide. Atherosclerosis promotes CVD through plaque formation, restricted blood flow, and thrombotic events. Macrophage accumulation in plaques, their uptake of cholesterol, and subsequent local death drive disease progression, however, there is growing appreciation for more diverse roles of myeloid cells during disease progression. Here, we focused on characterization of so-called vascular dendritic cells (DCs), which we refer to as aortic mononuclear phagocytes (MNP), that reside under the endothelium in plaque-prone areas. Using en face whole-mount confocal microscopy of aortas, we confirm a uniform resident CD11c+ CX3CR1+ MHCII+ MNP population, even in C57/BL6 mice resistant to atherosclerosis. We find aortic MNPs require M-CSF and Flt3 signaling for survival, but are independent of CCR2 and GM-CSF receptor signaling, making them a distinct myeloid population. They express macrophage-restricted genes LysM and CD64, but not dendritic cell specific genes zBTB46 or L-myc. Lineage-tracing analysis using CD115creER and Flt3cre reporter mice indicate that aortic MNPs likely differentiate from definitive hematopoiesis and not early yolk sac progenitors. Parabiosis experiments show that aortic MNPs are self-maintained independent of blood-born progenitors, failing to exchange with blood progenitors for up to 5 months. Aortic MNPs are different from either typical DCs or macrophages and instead appear to blend distinguishing features of each, more closely resembling macrophages. Using our characterization data, we hope to develop an inducible cell-tracking and a cell-depletion model to differentiate the function of aortic MNPs during the progression of atherosclerosis. Overall, we anticipate these functional analyses will reveal, for the first time, the role of resident aortic MNPs in atherosclerosis.

scholarly journals FAP Beige Adipogenesis in Volumetric Muscle Loss

2020 ◽  
Author(s):  
Zili Wang ◽  
Carlin S. Lee ◽  
Jinshen He ◽  
Kunqi Jiang ◽  
Mengyao Liu ◽  
...  
Keyword(s):  
Muscle Regeneration ◽  
Muscle Loss ◽  
Limb Function ◽  
Positive Role ◽  
Permanent Disability ◽  
Mouse Muscle ◽  
Volumetric Muscle Loss ◽  
Reporter Mice ◽  
Gfp Reporter

Abstract Background Volumetric muscle loss (VML) often leads to chronic muscle weakness, impaired limb function, and even permanent disability. Recent studies suggest muscle residential fibro/adipogenic progenitors (FAPs) can adopt novel beige fat differentiation promoting muscle regeneration. The goal of this study is to define the role of FAP beige adipogenesis in muscle regeneration after VML in a mouse model.Methods Three months old male C57BL/6J mice, PDGFRα-GFP reporter mice, UCP-1 reporter mice, PDGFRα-CREERT/DTA inducible FAP depletion mice and NSG immune-deficient mice were used in this study. Volumetric muscle loss (VML) was created on tibialis anterior (TA) muscle with a punch. To induce FAP beige adipogenesis, Amibegron, a beta 3 adrenergic receptor (B3AR) agonist was administered to mice with I.P. injection. In a separate group, murine and human beige adipogenic FAPs was transplanted to mouse muscle after VML. Limb function was measured with gait analysis at 2 and 6 weeks after VML. Muscle histology and FAP gene expression analysis was also conducted at 2 and 6 weeks after VML.Results After VML, we observed robust proliferation of FAPs in PDGFRα-GFP reporter mice. PDGFRα-CREERT/DTA mice inducible FAP depletion mice showed reduced muscle regeneration after FAPs are depleted, suggesting a positive role of FAP in muscle regeneration after VML. Both Amibegron treatment and beige FAP transplantation significantly improved muscle regeneration and limb function after VML.Conclusion Stimulating FAP beige adipogenesis with B3AR agonists or transplantation of beige adipogenic FAPs could serve as new strategies in treating VML.

Meiotic CENP-C is a shepherd: bridging the space between the centromere and the kinetochore in time and space

2020 ◽  
Vol 64 (2) ◽  
pp. 251-261
Author(s):  
Jessica E. Fellmeth ◽  
Kim S. McKim
Keyword(s):  
Chromosome Segregation ◽  
New Technologies ◽  
Early Prophase ◽  
Unique Role ◽  
Kinetochore Assembly ◽  
M Phase ◽  
In Vivo Analysis ◽  
Meiosis I

Abstract While many of the proteins involved in the mitotic centromere and kinetochore are conserved in meiosis, they often gain a novel function due to the unique needs of homolog segregation during meiosis I (MI). CENP-C is a critical component of the centromere for kinetochore assembly in mitosis. Recent work, however, has highlighted the unique features of meiotic CENP-C. Centromere establishment and stability require CENP-C loading at the centromere for CENP-A function. Pre-meiotic loading of proteins necessary for homolog recombination as well as cohesion also rely on CENP-C, as do the main scaffolding components of the kinetochore. Much of this work relies on new technologies that enable in vivo analysis of meiosis like never before. Here, we strive to highlight the unique role of this highly conserved centromere protein that loads on to centromeres prior to M-phase onset, but continues to perform critical functions through chromosome segregation. CENP-C is not merely a structural link between the centromere and the kinetochore, but also a functional one joining the processes of early prophase homolog synapsis to late metaphase kinetochore assembly and signaling.

Social Motives Predict Loneliness During a Developmental Transition

2017 ◽  
Vol 76 (4) ◽  
pp. 145-153 ◽  
Author(s):  
Jana Nikitin ◽  
Alexandra M. Freund
Keyword(s):  
Social Relationships ◽  
Well Being ◽  
Social Avoidance ◽  
Social Approach ◽  
Social Motives ◽  
Developmental Transitions ◽  
Avoidance Motivation ◽  
Negative Effect ◽  
Low Levels

Abstract. Establishing new social relationships is important for mastering developmental transitions in young adulthood. In a 2-year longitudinal study with four measurement occasions (T1: n = 245, T2: n = 96, T3: n = 103, T4: n = 85), we investigated the role of social motives in college students’ mastery of the transition of moving out of the parental home, using loneliness as an indicator of poor adjustment to the transition. Students with strong social approach motivation reported stable and low levels of loneliness. In contrast, students with strong social avoidance motivation reported high levels of loneliness. However, this effect dissipated relatively quickly as most of the young adults adapted to the transition over a period of several weeks. The present study also provides evidence for an interaction between social approach and social avoidance motives: Social approach motives buffered the negative effect on social well-being of social avoidance motives. These results illustrate the importance of social approach and social avoidance motives and their interplay during developmental transitions.

Social and Temporal Comparisons as Moderators of Psychological Resources Associations With Wellbeing

2016 ◽  
Vol 37 (2) ◽  
pp. 96-104 ◽  
Author(s):  
Hasida Ben-Zur
Keyword(s):  
Life Satisfaction ◽  
Positive Affect ◽  
Subjective Wellbeing ◽  
Social Comparisons ◽  
Self Esteem ◽  
Psychological Resources ◽  
Low Levels ◽  
Age Range ◽  
General Wellbeing

Abstract. The current study investigated the associations of psychological resources, social comparisons, and temporal comparisons with general wellbeing. The sample included 142 community participants (47.9% men; age range 23–83 years), who compared themselves with others, and with their younger selves, on eight dimensions (e.g., physical health, resilience). They also completed questionnaires assessing psychological resources of mastery and self-esteem, and three components of subjective wellbeing: life satisfaction and negative and positive affect. The main results showed that high levels of psychological resources contributed to wellbeing, with self-enhancing social and temporal comparisons moderating the effects of resources on certain wellbeing components. Specifically, under low levels of mastery or self-esteem self-enhancing social or temporal comparisons were related to either higher life satisfaction or positive affect. The results highlight the role of resources and comparisons in promoting people’s wellbeing, and suggest that self-enhancing comparisons function as cognitive coping mechanisms when psychological resources are low.

142-OR: Unique Role of the a4 Component for S6-Kinase Activity in Metabolic Regulation and Anti-apoptotic Effect in Brown Adipose Tissue

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 142-OR
Author(s):  
MASAJI SAKAGUCHI ◽  
SHOTA OKAGAWA ◽  
SAYAKA KITANO ◽  
TATSUYA KONDO ◽  
EIICHI ARAKI
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Metabolic Regulation ◽  
Kinase Activity ◽  
S6 Kinase ◽  
Unique Role ◽  
Brown Adipose ◽  
Apoptotic Effect

Ups and downs on the roller coaster of task conflict: the role of group cognitive complexity, collective emotional intelligence and team creativity

2020 ◽  
Vol 18 (1) ◽  
pp. 23-37
Author(s):  
Andreea Gheorghe ◽  
Oana Fodor ◽  
Anișoara Pavelea
Keyword(s):  
Emotional Intelligence ◽  
Cognitive Complexity ◽  
Empirical Support ◽  
Task Conflict ◽  
Team Creativity ◽  
Mediating Role ◽  
Low Levels ◽  
Explanatory Mechanism ◽  
The Relationship

This study explores the association between task conflict and team creativity and the role of group cognitive complexity (GCC) as a potential explanatory mechanism in a sample of 159 students organized in 49 groups. Moreover, we analyzed the moderating effect of collective emotional intelligence (CEI)in the relationship between task conflict and GCC.As hypothesized, we found that task conflict has a nonlinear relationship with GCC, but contrary to our expectations, it follows a U-shaped association, not an inversed U-shape. In addition,the moderating role of CEI was significant only at low levels. Contrary to our expectation, the mediating role of GCC did not receive empirical support. Theoretical and practical contributions are discussed.

scholarly journals Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321731
Author(s):  
Dominik Aschenbrenner ◽  
Maria Quaranta ◽  
Soumya Banerjee ◽  
Nicholas Ilott ◽  
Joanneke Jansen ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Personalised Medicine ◽  
Mononuclear Phagocytes ◽  
Cytokine Network ◽  
Peripheral Blood Mononuclear ◽  
Transcriptional Signature ◽  
Inflammatory Monocytes ◽  
Transcriptomic Signature ◽  
Inflammatory Bowel

ObjectiveDysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine.DesignWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples.ResultsWe characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.ConclusionOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.

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