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Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Unlu G, Qi X, Gamazon ER, Melville DB, Patel N, Rushing AR, Hashem M, Al-Faifi A, Chen R, Li B, Cox NJ, Alkuraya FS, Knapik EW
(2020) Nat Med 26: 98-109
MeSH Terms: Abnormalities, Multiple, Animals, Behavior, Animal, Biological Specimen Banks, Chondrocytes, Disease Models, Animal, Extracellular Matrix, Fibroblasts, Guanine Nucleotide Exchange Factors, Humans, Models, Biological, Musculoskeletal System, Osteogenesis, Phenomics, Phenotype, Procollagen, Protein Transport, Secretory Pathway, Syndrome, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 15, 2020
Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.
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21 MeSH Terms
Loss of flow responsive Tie1 results in Impaired
Aortic valve remodeling.
Qu X, Violette K, Sewell-Loftin MK, Soslow J, Saint-Jean L, Hinton RB, Merryman WD, Baldwin HS
(2019) Dev Biol 455: 73-84
MeSH Terms: Animals, Aortic Valve, Endothelial Cells, Extracellular Matrix, Female, Gene Expression Profiling, Gene Expression Regulation, Developmental, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Organogenesis, Pregnancy, Receptor, TIE-1, SOX9 Transcription Factor, Vascular Remodeling
Show Abstract · Added November 25, 2019
The mechanisms regulating endothelial cell response to hemodynamic forces required for heart valve development, especially valve remodeling, remain elusive. Tie1, an endothelial specific receptor tyrosine kinase, is up-regulated by oscillating shear stress and is required for lymphatic valve development. In this study, we demonstrate that valvular endothelial Tie1 is differentially expressed in a dynamic pattern predicted by disturbed flow during valve remodeling. Following valvular endocardial specific deletion of Tie1 in mice, we observed enlarged aortic valve leaflets, decreased valve stiffness and valvular insufficiency. Valve abnormalities were only detected in late gestation and early postnatal mutant animals and worsened with age. The mutant mice developed perturbed extracellular matrix (ECM) deposition and remodeling characterized by increased glycosaminoglycan and decreased collagen content, as well as increased valve interstitial cell expression of Sox9, a transcription factor essential for normal ECM maturation during heart valve development. This study provides the first evidence that Tie1 is involved in modulation of late valve remodeling and suggests that an important Tie1-Sox9 signaling axis exists through which disturbed flows are converted by endocardial cells to paracrine Sox9 signals to modulate normal matrix remodeling of the aortic valve.
Copyright © 2019. Published by Elsevier Inc.
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15 MeSH Terms
Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction.
Yao L, Wright MF, Farmer BC, Peterson LS, Khan AM, Zhong J, Gewin L, Hao CM, Yang HC, Fogo AB
(2019) Nephrol Dial Transplant 34: 2042-2050
MeSH Terms: Actins, Animals, Collagen Type I, Connective Tissue Growth Factor, Extracellular Matrix Proteins, Fibroblasts, Fibrosis, Kidney Diseases, Mice, Mice, Knockout, Nerve Tissue Proteins, Serpin E2, Transforming Growth Factor beta, Ureteral Obstruction
Show Abstract · Added March 18, 2020
BACKGROUND - Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1).
METHODS - Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later.
RESULTS - GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice.
CONCLUSION - These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.
© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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14 MeSH Terms
DSS-induced damage to basement membranes is repaired by matrix replacement and crosslinking.
Howard AM, LaFever KS, Fenix AM, Scurrah CR, Lau KS, Burnette DT, Bhave G, Ferrell N, Page-McCaw A
(2019) J Cell Sci 132:
MeSH Terms: Animals, Basement Membrane, Collagen Type IV, Dextran Sulfate, Drosophila melanogaster, Extracellular Matrix, Female, Laminin, Male
Show Abstract · Added March 27, 2019
Basement membranes are an ancient form of animal extracellular matrix. As important structural and functional components of tissues, basement membranes are subject to environmental damage and must be repaired while maintaining functions. Little is known about how basement membranes get repaired. This paucity stems from a lack of suitable models for analyzing such repair. Here, we show that dextran sodium sulfate (DSS) directly damages the gut basement membrane when fed to adult DSS becomes incorporated into the basement membrane, promoting its expansion while decreasing its stiffness, which causes morphological changes to the underlying muscles. Remarkably, two days after withdrawal of DSS, the basement membrane is repaired by all measures of analysis. We used this new damage model to determine that repair requires collagen crosslinking and replacement of damaged components. Genetic and biochemical evidence indicates that crosslinking is required to stabilize the newly incorporated repaired Collagen IV rather than to stabilize the damaged Collagen IV. These results suggest that basement membranes are surprisingly dynamic.
© 2019. Published by The Company of Biologists Ltd.
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9 MeSH Terms
Estradiol Treatment Initiated Early After Ovariectomy Regulates Myocardial Gene Expression and Inhibits Diastolic Dysfunction in Female Cynomolgus Monkeys: Potential Roles for Calcium Homeostasis and Extracellular Matrix Remodeling.
Michalson KT, Groban L, Howard TD, Shively CA, Sophonsritsuk A, Appt SE, Cline JM, Clarkson TB, Carr JJ, Kitzman DW, Register TC
(2018) J Am Heart Assoc 7: e009769
MeSH Terms: Animals, Calcium, Diastole, Estradiol, Extracellular Matrix, Female, Gene Expression, Heart, Homeostasis, Macaca fascicularis, Myocardium, Ovariectomy, Postoperative Period, Random Allocation, Time Factors
Show Abstract · Added January 10, 2020
Background Left ventricular ( LV ) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on LV function and myocardial gene expression in female cynomolgus macaques. Methods and Results Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a human-equivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of LV myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all P<0.05), despite similar estimated LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals ( P<0.05). Microarray analysis revealed differential myocardial expression of 40 genes (>1.2-fold change; false discovery rate, P<0.05) in estradiol animals relative to controls, which implicated pathways associated with better calcium ion homeostasis and muscle contraction and lower extracellular matrix deposition ( P<0.05). Conclusions Estradiol treatment initiated soon after ovariectomy resulted in enhanced LV diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function.
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MeSH Terms
Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model.
Colon S, Luan H, Liu Y, Meyer C, Gewin L, Bhave G
(2019) Am J Physiol Renal Physiol 316: F360-F371
MeSH Terms: Animals, Cell Movement, Disease Models, Animal, Eosinophil Peroxidase, Eosinophils, Extracellular Matrix Proteins, Female, Fibrosis, Kidney, Male, Mice, Inbred C57BL, Mice, Knockout, Nephritis, Interstitial, Peroxidase, Peroxidases, Reactive Oxygen Species, Signal Transduction, Ureteral Obstruction
Show Abstract · Added March 26, 2019
Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (HO). The animal heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPX), and peroxidasin (PXDN) uniquely metabolize HO into highly reactive and destructive hypohalous acids, such as hypobromous and hypochlorous acid. However, the role of these peroxidases and their downstream hypohalous acids in the pathogenesis of renal fibrosis is unclear. Our study defines the contribution of MPO, EPX, and PXDN to renal inflammation and tubulointerstitial fibrosis in the murine unilateral ureteral obstruction (UUO) model. Using a nonspecific inhibitor of animal heme peroxidases and peroxidase-specific knockout mice, we find that loss of EPX or PXDN, but not MPO, reduces renal fibrosis. Furthermore, we demonstrate that eosinophils, the source of EPX, accumulate in the renal interstitium after UUO. These findings point to EPX and PXDN as potential therapeutic targets for renal fibrosis and CKD and suggest that eosinophils modulate the response to renal injury.
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18 MeSH Terms
Traction Force Microscopy for Noninvasive Imaging of Cell Forces.
Mulligan JA, Bordeleau F, Reinhart-King CA, Adie SG
(2018) Adv Exp Med Biol 1092: 319-349
MeSH Terms: Biomechanical Phenomena, Extracellular Matrix, Humans, Microscopy, Atomic Force, Models, Biological
Show Abstract · Added April 10, 2019
The forces exerted by cells on their surroundings play an integral role in both physiological processes and disease progression. Traction force microscopy is a noninvasive technique that enables the in vitro imaging and quantification of cell forces. Utilizing expertise from a variety of disciplines, recent developments in traction force microscopy are enhancing the study of cell forces in physiologically relevant model systems, and hold promise for further advancing knowledge in mechanobiology. In this chapter, we discuss the methods, capabilities, and limitations of modern approaches for traction force microscopy, and highlight ongoing efforts and challenges underlying future innovations.
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5 MeSH Terms
The altered mechanical phenotype of fetal fibroblasts hinders myofibroblast differentiation.
Jerrell RJ, Leih MJ, Parekh A
(2019) Wound Repair Regen 27: 29-38
MeSH Terms: Adult, Cell Differentiation, Cells, Cultured, Cicatrix, Collagen Type III, Extracellular Matrix, Female, Fetus, Fibroblasts, Gene Expression Regulation, Humans, Male, Myofibroblasts, Phenotype, Pregnancy, Transforming Growth Factor beta1, Wound Healing, Young Adult
Show Abstract · Added March 18, 2020
During the dermal wound healing process, the mechanical rigidity of the newly deposited extracellular matrix and transforming growth factor-β1 promote the transition of fibroblasts into myofibroblasts. Myofibroblasts generate large cellular forces that contract and remodel the extracellular matrix leading to scar formation. In contrast, myofibroblasts are not detected in fetal dermal wounds which are more compliant and contain less transforming growth factor-β1 than adult wounds. Instead, fetal fibroblasts orchestrate scarless healing of dermal wounds resulting in healed tissues that resemble uninjured dermis. While these biomechanical differences suggest that the fetal wound environment promotes smaller cellular forces which enable regeneration, previous studies indicate that fetal fibroblasts have unique contractile properties that may facilitate scarless dermal repair. Therefore, we tested whether physiologic wound rigidities and transforming growth factor-β1 induce contractile forces and myofibroblast differentiation of fetal dermal fibroblasts. In comparison to their adult dermal counterparts, we found that fetal fibroblasts exhibit a deficient contractile response to rigid extracellular matrix and transforming growth factor-β1. Our data suggest that the contractile phenotype of fetal dermal fibroblasts limits their cellular force production and prevents their ability to differentiate into myofibroblasts.
© 2018 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound Healing Society.
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Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes.
McCall AS, Bhave G, Pedchenko V, Hess J, Free M, Little DJ, Baker TP, Pendergraft WF, Falk RJ, Olson SW, Hudson BG
(2018) J Am Soc Nephrol 29: 2619-2625
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Anti-Glomerular Basement Membrane Disease, Antibodies, Antineutrophil Cytoplasmic, Antibody Specificity, Autoantibodies, Autoantigens, Child, Cohort Studies, Collagen Type IV, Extracellular Matrix Proteins, Female, Glomerulonephritis, Hemorrhage, Humans, Lung Diseases, Male, Middle Aged, Models, Immunological, Peroxidase, Peroxidases, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP.
METHODS - We used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score.
RESULTS - We detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production . The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease.
CONCLUSIONS - Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.
Copyright © 2018 by the American Society of Nephrology.
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Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
Wang W, Lollis EM, Bordeleau F, Reinhart-King CA
(2019) FASEB J 33: 1199-1208
MeSH Terms: Adherens Junctions, Animals, Antigens, CD, Cadherins, Capillary Permeability, Chick Embryo, Endothelium, Vascular, Enzyme Activation, Extracellular Matrix, Female, Focal Adhesion Protein-Tyrosine Kinases, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Transgenic, Phosphorylation, Protein Transport, Tyrosine, src-Family Kinases
Show Abstract · Added April 10, 2019
Tumor vasculature is known to be more permeable than the vasculature found in healthy tissue, which in turn can lead to a more aggressive tumor phenotype and impair drug delivery into tumors. While the stiffening of the stroma surrounding solid tumors has been reported to increase vascular permeability, the mechanism of this process remains unclear. Here, we utilize an in vitro model of tumor stiffening, ex ovo culture, and a mouse model to investigate the molecular mechanism by which matrix stiffening alters endothelial barrier function. Our data indicate that the increased endothelial permeability caused by heightened matrix stiffness can be prevented by pharmaceutical inhibition of focal adhesion kinase (FAK) both in vitro and ex ovo. Matrix stiffness-mediated FAK activation determines Src localization to cell-cell junctions, which then induces increased vascular endothelial cadherin phosphorylation both in vitro and in vivo. Endothelial cells in stiff tumors have more activated Src and higher levels of phosphorylated vascular endothelial cadherin at adherens junctions compared to endothelial cells in more compliant tumors. Altogether, our data indicate that matrix stiffness regulates endothelial barrier integrity through FAK activity, providing one mechanism by which extracellular matrix stiffness regulates endothelial barrier function. Additionally, our work also provides further evidence that FAK is a promising potential target for cancer therapy because FAK plays a critical role in the regulation of endothelial barrier integrity.-Wang, W., Lollis, E. M., Bordeleau, F., Reinhart-King, C. A. Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
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19 MeSH Terms