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- Egana, I, et al.
(författare)
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Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 15453-
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Tidskriftsartikel (refereegranskat)abstract
- Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
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| 6. |
- Muhl, Lars, et al.
(författare)
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A single-cell transcriptomic inventory of murine smooth muscle cells
- 2022
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Ingår i: Developmental Cell. - : Elsevier. - 1534-5807 .- 1878-1551. ; 57:20, s. 2426-
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Tidskriftsartikel (refereegranskat)abstract
- Smooth muscle cells (SMCs) execute important physiological functions in numerous vital organ systems, including the vascular, gastrointestinal, respiratory, and urogenital tracts. SMC differ morphologically and functionally at these different anatomical locations, but the molecular underpinnings of the differences remain poorly understood. Here, using deep single-cell RNA sequencing combined with in situ gene and pro-tein expression analysis in four murine organs-heart, aorta, lung, and colon-we identify a molecular basis for high-level differences among vascular, visceral, and airway SMC, as well as more subtle differences between, for example, SMC in elastic and muscular arteries and zonation of elastic artery SMC along the direction of blood flow. Arterial SMC exhibit extensive organotypic heterogeneity, whereas venous SMC are similar across organs. We further identify a specific SMC subtype within the pulmonary vasculature. This comparative SMC cross-organ resource offers insight into SMC subtypes and their specific functions.
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| 7. |
- Muhl, Lars, et al.
(författare)
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Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Many important cell types in adult vertebrates have a mesenchymal origin, including fibroblasts and vascular mural cells. Although their biological importance is undisputed, the level of mesenchymal cell heterogeneity within and between organs, while appreciated, has not been analyzed in detail. Here, we compare single-cell transcriptional profiles of fibroblasts and vascular mural cells across four murine muscular organs: heart, skeletal muscle, intestine and bladder. We reveal gene expression signatures that demarcate fibroblasts from mural cells and provide molecular signatures for cell subtype identification. We observe striking inter- and intra-organ heterogeneity amongst the fibroblasts, primarily reflecting differences in the expression of extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) and regulatory signaling circuits. Our data shed new light on the diversity of poorly defined classes of cells and provide a foundation for improved understanding of their roles in physiological and pathological processes. To define and distinguish fibroblasts from vascular mural cells have remained challenging. Here, using single-cell RNA sequencing and tissue imaging, the authors provide a molecular basis for cell type classification and reveal inter- and intra-organ diversity of these cell types.
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| 8. |
- Pietilä, Riikka, et al.
(författare)
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Molecular anatomy of adult mouse leptomeninges
- 2023
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Ingår i: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 111:23
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Tidskriftsartikel (refereegranskat)abstract
- Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we iden-tify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arach-noid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.
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- Carthy, Jon M., et al.
(författare)
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Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.
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| 11. |
- Connick, Mark J., et al.
(författare)
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Cluster analysis of novel isometric strength measures produces a valid and evidence-based classification structure for wheelchair track racing
- 2018
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 52:17, s. 1123-1129
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Para athletics wheelchair-racing classification system employs best practice to ensure that classes comprise athletes whose impairments cause a comparable degree of activity limitation. However, decision-making is largely subjective and scientific evidence which reduces this subjectivity is required.AIM: To evaluate whether isometric strength tests were valid for the purposes of classifying wheelchair racers and whether cluster analysis of the strength measures produced a valid classification structure.METHODS: Thirty-two international level, male wheelchair racers from classes T51-54 completed six isometric strength tests evaluating elbow extensors, shoulder flexors, trunk flexors and forearm pronators and two wheelchair performance tests-Top-Speed (0-15 m) and Top-Speed (absolute). Strength tests significantly correlated with wheelchair performance were included in a cluster analysis and the validity of the resulting clusters was assessed.RESULTS: All six strength tests correlated with performance (r=0.54-0.88). Cluster analysis yielded four clusters with reasonable overall structure (mean silhouette coefficient=0.58) and large intercluster strength differences. Six athletes (19%) were allocated to clusters that did not align with their current class. While the mean wheelchair racing performance of the resulting clusters was unequivocally hierarchical, the mean performance of current classes was not, with no difference between current classes T53 and T54.CONCLUSIONS: Cluster analysis of isometric strength tests produced classes comprising athletes who experienced a similar degree of activity limitation. The strength tests reported can provide the basis for a new, more transparent, less subjective wheelchair racing classification system, pending replication of these findings in a larger, representative sample. This paper also provides guidance for development of evidence-based systems in other Para sports.
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| 14. |
- Muhl, Lars, et al.
(författare)
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The SARS-CoV-2 receptor ACE2 is expressed in mouse pericytes but not endothelial cells : Implications for COVID-19 vascular research
- 2022
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Ingår i: Stem Cell Reports. - : Elsevier. - 2213-6711. ; 17:5, s. 1089-1104
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Tidskriftsartikel (refereegranskat)abstract
- Humanized mouse models and mouse-adapted SARS-CoV-2 virus are increasingly used to study COVID-19 pathogenesis, so it is impor-tant to learn where the SARS-CoV-2 receptor ACE2 is expressed. Here we mapped ACE2 expression during mouse postnatal development and in adulthood. Pericytes in the CNS, heart, and pancreas express ACE2 strongly, as do perineurial and adrenal fibroblasts, whereas endothelial cells do not at any location analyzed. In a number of other organs, pericytes do not express ACE2, including in the lung where ACE2 instead is expressed in bronchial epithelium and alveolar type II cells. The onset of ACE2 expression is organ specific: in bronchial epithelium already at birth, in brain pericytes before, andin heart pericytes after postnatal day 10.5. Establishing the vascular localization of ACE2 expression is central to correctly interpret data from modeling COVID-19 in the mouse and may shed light on the cause of vascular COVID-19 complications.
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| 15. |
- Niaudet, Colin, et al.
(författare)
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Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysemalike pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.
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| 16. |
- Petkova, Milena, et al.
(författare)
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Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
- 2023
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:4
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Tidskriftsartikel (refereegranskat)abstract
- Oncogenic mutations in PIK3CA, encoding p110α-PI3K, are a common cause of venous and lymphatic malformations. Vessel type–specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C–producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.
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| 17. |
- Rosso, V., et al.
(författare)
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Evaluating objective measures of impairment to trunk strength and control for cross-country sit skiing
- 2021
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Ingår i: Sports Engineering. - : Springer Science and Business Media LLC. - 1369-7072 .- 1460-2687. ; 24:6
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Tidskriftsartikel (refereegranskat)abstract
- In Paralympic cross-country sit skiing, athlete classification is performed by an expert panel, so it may be affected by subjectivity. An evidence-based classification is required, in which objective measures of impairment must be identified. The purposes of this study were: (i) to evaluate the reliability of 5 trunk strength measures and 18 trunk control measures developed for the purposes of classification; (ii) to rank the objective measures, according to the largest effects on perfor-mance. Using a new testing device, 14 elite sit-skiers performed two upright seated press tests and one simulated poling test to evaluate trunk strength. They were also subjected to unpredictable balance perturbations to measure trunk control. Tests were repeated on two separate days and test–retest reliability of trunk strength and trunk control measures was evaluated. A cluster analysis was run and correlation was evaluated, including all strength and control measures, to identify the measures that contributed most to clustering participants. Intraclass correlations coefficients (ICC) were 0.71 < ICC < 0.98 and 0.83 < ICC < 0.99 for upright seated press and perturbations, respectively. Cluster analysis identified three clusters with relevance for strength and balance control measures. For strength, in upright seated press peak anterior pushing force without backrest (effect size = 0.77) and ratio of peak anterior pushing force without and with backrest (effect size = 0.72) were significant. For balance control measures, trunk range of motion in forward (effect size = 0.81) and backward (effect size = 0.75) perturbations also contributed. High correlations (− 0.76 < r < − 0.53) were found between strength and control measures. The new testing device, protocol, and the cluster analysis show promising results in assessing impairment of trunk strength and control to empower an evidence-based classification.
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| 18. |
- Rosso, V., et al.
(författare)
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Simulated skiing as a measurement tool for performance in cross-country sit-skiing
- 2019
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Ingår i: Proceedings of the Institution of Mechanical Engineers Part P-Journal of Sports Engineering and Technology. - : SAGE Publications. - 1754-3371 .- 1754-338X. ; 233:4, s. 455-466
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Tidskriftsartikel (refereegranskat)abstract
- The International Paralympic Committee mandates the development of an evidence-based classification system, which requires a measure of performance. Performance in cross-country sit-skiing is mainly dependent on force generated during the poling phase and is enhanced by trunk flexion-extension movements. Since all sit-skiers have neuromuscular impairment, but different ability to control the trunk, this study aimed to verify if simulated action of poling on an adapted ergometer, together with a cluster analysis, could be used for grouping participants with different impairments according to their performance. On the ergometer, eight male and five female participants performed seven poling cycles at maximal speed, while sitting on personal sit-ski. Based on maximal speed, generated force, cycle characteristics, and trunk kinematics, cluster analysis divided participants into three groups showing good accuracy, sensitivity, and precision. Although a validation of this exploratory study is necessary, skiing on the ergometer could be considered as sport-specific measure of performance and may become an interesting tool in the development of an evidence-based classification system for cross-country sit-skiing.
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