bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.04.20.051045

Cadherin-6 mediates thrombosis in vivo

Bouck, E. G.·de la Fuente, M.·Zunica, E. R.·Li, W.·Mumaw, M. M.·Nieman, M. T.
View original source ↗Export metadata ↓

Abstract

Background Platelet adhesion is the critical process mediating stable thrombus formation. Previous reports of cadherin-6 on human platelets have demonstrated its role in platelet aggregation and thrombus formation.Objectives We aimed to further characterize the importance of cadherin-6 in thrombosis in vivo.Methods Cadherin-6 platelet expression was evaluated by western blotting, flow cytometry and immunoprecipitation. Thrombosis was evaluated using the FeCl3 and Rose Bengal carotid artery models in C57Bl6 mice treated with anti-cadherin-6 or IgG and wild-type or Cdh6-/- mice. Platelet function was compared in wild type and Cdh6-/- mice using tail-clip assays and aggregometry.Results Human platelet expression of cadherin-6 was confirmed at ~3,000 copies per platelet. Cdh6-/- mice or those treated with anti-Cadherin-6 antibody showed an increased time to occlusion in both thrombosis models. Cadherin-6 was not expressed on mouse platelets, and there were no differences in tail bleeding times or platelet aggregation in wild-type versus Cdh6-/- mice.Conclusions Cadherin-6 plays an essential role in thrombosis in vivo. However, cadherin-6 is not expressed on murine platelets. These data are in contrast to human platelets, which express a functional cadherin-6/catenin complex. The essential, platelet-independent role for cadherin-6 in hemostasis may allow it to be an effective and safe therapeutic target.EssentialsCadherin-6 function in thrombus formation was investigated in vivo using two murine models of thrombosis.Blocking or deleting cadherin-6 significantly delayed time to occlusionHuman platelets express cadherin-6, but murine platelets do not.Competing Interest StatementThe authors have declared no competing interest.View Full Text

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Bouck, E. G., de la Fuente, M., Zunica, E. R., Li, W., Mumaw, M. M., Nieman, M. T.. 2020-04-21. Cadherin-6 mediates thrombosis in vivo. https://doi.org/10.1101/2020.04.20.051045

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

SilencioM: silencing connected interfering oligonucleotides against MAPT as a potential disease modifying therapeutic for tauopathies

Tauopathies are a diverse group of neurodegenerative diseases whose pathogenesis involves brain accumulation of misfolded, pathological tau (Microtubule Associated Protein Tau, MAPT). More than twenty tauopathies have been identified thus far that collectively impact millions of people worldwide, of which the most common is Alzheimer's disease (AD). Despite substantial efforts to develop drugs for tauopathies, no effective treatments currently exist, highlighting the urgent need for therapeutics to combat these prevalent and ruinous neurodegenerative diseases. Strategies that target tau are likely to have the greatest impact since tau is the proximal cause of their pathogenesis. Small interfering RNAs (siRNAs) have emerged as a powerful class of precision therapeutics that silence disease-causing genes through RNA interference with favorable safety profiles. Delivery challenges are rapidly being addressed, and siRNA-based approaches are poised to transform the therapeutic landscape of neurological diseases. In this study, we describe SilencioM (Silencing connected interfering oligonucleotides against MAPT) and show its efficacy in markedly reducing tau pathology after a single intracerebroventricular injection in PS19 mice, a mouse model of severe tauopathy. SilencioM targets human, primate, rat and mouse ortholog genes; thus, the same compound can proceed from efficacy studies to Investigational New Drug Application (IND)-enabling studies. SilencioM is simple to manufacture and is administered without encapsulation in lipid nanoparticles and without requirements for lipophilic conjugation, making it a promising candidate for further development as a novel therapeutic for tauopathies, including AD.

pathology↗
bioRxiv2026

Relative expression of THY1 and PDGFRA in equine endometrosis in relation to severity, histopathological features and endometrial transcripts

Equine endometrosis is a degenerative uterine disease characterized by periglandular fibrosis and represents a major cause of subfertility in mares. While stromal cell activation results in pathological tissue remodeling, the involvement of cell-surface integrators (THY1) and growth factor receptors (PDGFRA) was not researched. This study evaluated the relative mRNA expression of THY1 and PDGFRA across Kenney and Doig (KD) endometrosis categories and specific histopathological features. Additionally, transcriptomic correlation profiles between target genes and markers of myofibroblast differentiation (ACTA2), cellular proliferation (MKI67), and steroid hormone receptors (ESR1, PGR) were analyzed. Endometrial samples (n = 47) were quantified using RT-qPCR. Relative mRNA expression of THY1 differed significantly across KD categories (p = 0.014), exhibiting a transient upregulation in category IIA compared with category I (p = 0.009) and category IIB (p = 0.002). Furthermore, THY1 relative mRNA expression was significantly elevated in tissues with glandular basal lamina disruption (p = 0.022). Conversely, PDGFRA relative mRNA expression remained stable across disease categories (p > 0.05). THY1 relative mRNA expression correlated very strongly with ACTA2 ({rho} = 0.875, p < 0.001) and strongly with ESR1 ({rho} = 0.652, p < 0.001). PDGFRA relative mRNA expression exhibited a very strong positive correlation with ESR1 ({rho} = 0.864, p < 0.001) and a strong positive correlation with MKI67 ({rho} = 0.674, p < 0.001). These results indicate that THY1 transcription is transiently induced during early stromal remodeling and basal lamina loss, whereas PDGFRA maintains constitutive transcript stability. Observed co-expression profiles reflect statistical co-variation among stromal remodeling, proliferative, and steroid-responsive cell populations in bulk tissue.

pathology↗
bioRxiv2026

CD8+ T-cells protect against experimental atherosclerosis through antigen specific interactions in the plaque

Atherosclerosis is a chronic inflammatory disease with a significant adaptive immune component. CD8+ T cells accumulate in plaques and display signatures of antigen-specific activation. However, whether this accumulation is driven by local antigen recognition and what functional consequences follow, remains poorly understood. Here we address this gap of knowledge using loss- and gain-of-function experiments. Atherosclerotic Rag-/-Ldlr-/- mice received adoptively transferred wildtype or antigen-restricted CD8+ T cells alongside CD4+ T cells to distinguish antigen-specific from antigen-independent responses. In a complementary model, ApobOVA-TGxLdlr-/- mice, expressing an ovalbumin-tagged variant of the atherosclerosis-associated ApoB100 protein, enabled OT-I CD8+ T cells to function as atherosclerosis-antigen-specific CD8+ T cells. T-cell distribution, activation and phenotype were assessed systemically and within lesions, plaque burden and composition were quantified histologically. Wildtype CD8+ T cells accumulated significantly more in aortic lesions compared to antigen-restricted CD8+ T cells, and exhibited increased activation, exhaustion and cytokine secretion, indicating that plaque-infiltrating T cells are predominantly antigen-specific. Perturbing antigen-specific CD8+ T-cell interactions significantly decreased plaque stability index, suggesting a protective role for antigen-specific CD8+ T cells. In ApobOVA-TGxLdlr-/- mice, OT-I T cells accumulated at high frequency in the liver, consistent with hepatic ApoB100-expression, and were found in circulation and aorta. Histological analysis revealed reduced plaque burden in OT-I recipients, reproducing an atheroprotective effect of antigen-specific CD8+ T-cell responses. Plaque reduction coincided with reduced TUNEL, but similar Caspase 3 staining, suggesting OT-I transfer results in reduced secondary necrosis. In line with this, CD47 expression in OT-I recipient mice was reduced and in vitro, OT-I but not antigen non-specific CD8+ T cells reduced expression of CD47 on OVA-presenting foam cells. CD8+ T-cell accumulation in experimental atherosclerosis is driven primarily by antigen-specific interactions and such responses are associated with plaque stabilization and reduced lesion formation, potentially through induction of apoptosis and prevention of secondary necrosis

pathology↗