Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor β (TGF-β) family of ligands. Although required for normal heart valve ...development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
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•Induction of EndoMT triggers a reduction in FAO•FAO is required to maintain endothelial acetyl-CoA levels•FAO modulates in vitro and in vivo EndoMT
Xiong et al. demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of endothelial-to-mesenchymal transition (EndoMT) and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which ...accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.
Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CL/P), the most frequent ...human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CL/P in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CL/P and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CL/P. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair.
► Pbx genes promote midfacial morphogenesis via direct activation of Wnt9b-Wnt3 ► A Pbx-Wnt-p63-Irf6 module induces apoptosis at the embryonic lambdoidal junction (λ) ► Disruption of the Pbx-Wnt-p63-Irf6 module, conserved in mammals, causes cleft lip ► Ectopic Wnt1 expression can rescue genetically cleft lip in Pbx mutants
Here, we describe a novel pathogenic entity, the activated PMN (polymorphonuclear leukocyte, i.e., neutrophil)-derived exosome. These CD63+/CD66b+ nanovesicles acquire surface-bound neutrophil ...elastase (NE) during PMN degranulation, NE being oriented in a configuration resistant to α1-antitrypsin (α1AT). These exosomes bind and degrade extracellular matrix (ECM) via the integrin Mac-1 and NE, respectively, causing the hallmarks of chronic obstructive pulmonary disease (COPD). Due to both ECM targeting and α1AT resistance, exosomal NE is far more potent than free NE. Importantly, such PMN-derived exosomes exist in clinical specimens from subjects with COPD but not healthy controls and are capable of transferring a COPD-like phenotype from humans to mice in an NE-driven manner. Similar findings were observed for another neutrophil-driven disease of ECM remodeling (bronchopulmonary dysplasia BPD). These findings reveal an unappreciated role for exosomes in the pathogenesis of disorders of ECM homeostasis such as COPD and BPD, providing a critical mechanism for proteolytic damage.
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•Exosomes from activated, not quiescent, PMNs harbor surface α1AT-insensitive NE•Activated PMN exosomes bind ECM via MAC-1 and degrade ECM via NE•CD66b+/NE+ PMN exosomes cause emphysema and RVH when administered to mice•CD66b+/NE+ PMN exosomes reside in COPD patients and transfer a COPD phenotype to mice
In chronic inflammatory lung disease, neutrophil-derived pathogenic exosomes bypass the pulmonary antiprotease barrier to promote extracellular matrix destruction.
MMP generated matrikines Wells, J. Michael; Gaggar, Amit; Blalock, J. Edwin
Matrix biology,
05/2015, Letnik:
44-46
Journal Article
Recenzirano
Odprti dostop
Matrikines originate from the fragmentation of extracellular matrix proteins and regulate cellular activities by interacting with specific receptors. Matrikines are implicated in inflammation, immune ...responses, organ development, wound repair, angiogenesis, atherosclerosis, tumor progression and metastasis due to their ability to alter cellular migration, chemotaxis, and mitogenesis. Matrix metalloproteinases (MMPs) degrade extracellular matrix components under normal circumstances and in disease processes. Of the 20 MMPs identified, MMP-1, MMP-2, MMP-8, MMP-9, and MMP-12 have been implicated in regulating the matrikines Val-Gly-Val-Ala-Pro-Gly (elastin peptide) and proline–glycine–proline (PGP). Elastin peptide fragments are generated by elastolytic enzymes and have implications in atherosclerosis, neovascularization, chronic obstructive pulmonary disease, skin disease, as well as tumor invasion and spread. PGP is produced through a multistep pathway that liberates the tripeptide fragment from extracellular collagen. PGP is best described for its role in neutrophil chemotaxis and is implicated in the pathogenesis of corneal ulcers and in chronic lung conditions. In chronic cigarette smoke related lung disease, the PGP pathway can become a self-propagating cycle of inflammation through cigarette-smoke mediated inhibition of leukotriene A4 hydrolase, the enzyme responsible for degrading PGP and halting acute inflammation. This review highlights the roles of MMPs in generating these important matrikines.
•MMPs degrade extracellular matrix and regulate several matrikines.•MMP-generated matrikines have effects in cancer, vascular disease, and lung disease.•The elastin peptide (VGVAPG) increases expression of MMPs in connective tissues.•MMPs are crucial to generation of the matrikine PGP from ECM collagen.•PGP is a cigarette-smoke mediated neutrophil chemoattractant found in COPD.
Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely ...understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B
mouse model of ASD. Male and female Shank3B
mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.
In this study, the investigators found a strong association, in two cohorts, between future exacerbations of COPD and the ratio of the diameter of the pulmonary artery to the diameter of the aorta ...(with both diameters measured from a baseline CT scan) that is greater than 1.
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are critical events in the natural history of the disease and are associated with accelerated loss of lung function and poor quality of life.
1
,
2
Hospitalizations for exacerbations account for $18 billion in direct costs annually in the United States and are associated with 1-year mortality of 21% and 5-year mortality of 55%.
3
Identification of patients at risk for these events is therefore of major importance.
Acute exacerbations of COPD are defined as an increase in dyspnea, cough, or sputum production warranting a change in therapy. These acute exacerbations often result from . . .
Cor pulmonale (right ventricular RV dilation) and cor pulmonale parvus (RV shrinkage) are both described in chronic obstructive pulmonary disease (COPD). The identification of emphysema as a shared ...risk factor suggests that additional disease characterization is needed to understand these widely divergent cardiac processes.
To explore the relationship between computed tomography measures of emphysema and distal pulmonary arterial morphology with RV volume, and their association with exercise capacity and mortality in ever-smokers with COPD enrolled in the COPDGene Study.
Epicardial (myocardium and chamber) RV volume (RV
), distal pulmonary arterial blood vessel volume (arterial BV5: vessels <5 mm
in cross-section), and objective measures of emphysema were extracted from 3,506 COPDGene computed tomography scans. Multivariable linear and Cox regression models and the log-rank test were used to explore the association between emphysema, arterial BV5, and RV
with exercise capacity (6-min-walk distance) and all-cause mortality.
The RV
was approximately 10% smaller in Global Initiative for Chronic Obstructive Lung Disease stage 4 versus stage 1 COPD (
< 0.0001). In multivariable modeling, a 10-ml decrease in arterial BV5 (pruning) was associated with a 1-ml increase in RV
. For a given amount of emphysema, relative preservation of the arterial BV5 was associated with a smaller RV
. An increased RV
was associated with reduced 6-minute-walk distance and in those with arterial pruning an increased mortality.
Pulmonary arterial pruning is associated with clinically significant increases in RV volume in smokers with COPD and is related to exercise capacity and mortality in COPD.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are ...common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs). NCCs recombined with HIOs in vitro migrated into the mesenchyme, differentiated into neurons and glial cells and showed neuronal activity, as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, had functional interstitial cells of Cajal and had an electromechanical coupling that regulated waves of propagating contraction. Finally, we used this system to investigate the cellular and molecular basis for Hirschsprung's disease caused by a mutation in the gene PHOX2B. This is, to the best of our knowledge, the first demonstration of human-PSC-derived intestinal tissue with a functional ENS and how this system can be used to study motility disorders of the human gastrointestinal tract.
Xing and Wells discuss the development of a potential novel treatment for emphysema, a hallmark of chronic obstructive pulmonary disease (COPD). Emphysema is characterized by the loss of lung ...architecture and destruction of lung tissue. Current therapies for COPD focus on treating the symptoms and complications of the disease rather than targeting the underlying mechanisms of emphysema development. The study by Soto et al explores the use of two protein phosphatase 2A (PP2A) activators as potential therapeutics for emphysema. PP2A is a serine-threonine phosphatase that plays a crucial role in various cellular processes. They tested the PP2A activators in human bronchial epithelial cells and in a model of cigarette smoke-induced emphysema. They found that the activators activated PP2A and decreased signaling pathways associated with emphysema. Treatment with the activators prevented loss of lung function and emphysema progression in the model. The study suggests that PP2A activation holds promise for addressing the underlying mechanisms of COPD and potentially slowing down the progression of emphysema. Further research is needed to assess the safety and efficacy of these activators in human clinical trials.
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