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Dual role for CXCL12 signaling in semilunar valve development.

ABSTRACT: Cxcl12-null embryos have dysplastic, misaligned, and hyperplastic semilunar valves (SLVs). In this study, we show that CXCL12 signaling via its receptor CXCR4 fulfills distinct roles at different stages of SLV development, acting initially as a guidance cue to pattern cellular distribution within the valve primordia during the endocardial-to-mesenchymal transition (endoMT) phase and later regulating mesenchymal cell proliferation during SLV remodeling. Transient, anteriorly localized puncta of internalized CXCR4 are observed in cells undergoing endoMT. In vitro, CXCR4⁺ cell orientation in response to CXCL12 requires phosphatidylinositol 3-kinase (PI3K) signaling and is inhibited by suppression of endocytosis. This dynamic intracellular localization of CXCR4 during SLV development is related to CXCL12 availability, potentially enabling activation of divergent downstream signaling pathways at key developmental stages. Importantly, Cxcr7^-/- mutants display evidence of excessive CXCL12 signaling, indicating a likely role for atypical chemokine receptor CXCR7 in regulating ligand bioavailability and thus CXCR4 signaling output during SLV morphogenesis.

SUBMITTER: Ridge LA

PROVIDER: S-EPMC8411116 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Dual role for CXCL12 signaling in semilunar valve development.

Ridge Liam A LA Kewbank Dania D Schütz Dagmar D Stumm Ralf R Scambler Peter J PJ Ivins Sarah S

Cell reports 20210801 8

Cxcl12-null embryos have dysplastic, misaligned, and hyperplastic semilunar valves (SLVs). In this study, we show that CXCL12 signaling via its receptor CXCR4 fulfills distinct roles at different stages of SLV development, acting initially as a guidance cue to pattern cellular distribution within the valve primordia during the endocardial-to-mesenchymal transition (endoMT) phase and later regulating mesenchymal cell proliferation during SLV remodeling. Transient, anteriorly localized puncta of i ...[more]

PMID: 34433040

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Project description:Semilunar valve malformations are common human congenital heart defects. Bicuspid aortic valves occur in 2-3% of the population, and pulmonic valve stenosis constitutes 10% of all congenital heart disease in adults (Brickner et al., 2000) [1]. Semilunar valve defects cause valve regurgitation, stenosis, or calcification, leading to endocarditis or congestive heart failure. These complications often require prolonged medical treatment or surgical intervention. Despite the medical importance of valve disease, the regulatory pathways governing semilunar valve development are not entirely clear. In this report we investigated the spatiotemporal role of calcineurin/Nfatc1 signaling in semilunar valve development. We generated conditional knockout mice with calcineurin gene disrupted in various tissues during semilunar valve development. Our studies showed that calcineurin/Nfatc1 pathway signals in the secondary heart field (SHF) but not in the outflow tract myocardium or neural crest cells to regulate semilunar valve morphogenesis. Without SHF calcineurin/Nfatc1 signaling, the conal endocardial cushions-the site of prospective semilunar valve formation--first develop and then regress due to apoptosis, resulting in a striking phenotype with complete absence of the aortic and pulmonic valves, severe valve regurgitation, and perinatal lethality. This role of calcineurin/Nfatc1 signaling in the SHF is different from the requirement of calcineurin/Nfatc1 in the endocardium for semilunar valve formation (Chang et al., 2004) [2], indicating that calcineurin/Nfatc1 signals in multiple tissues to organize semilunar valve development. Also, our studies suggest distinct mechanisms of calcineurin/Nfat signaling for semilunar and atrioventricular valve morphogenesis. Therefore, we demonstrate a novel developmental mechanism in which calcineurin signals through Nfatc1 in the secondary heart field to promote semilunar valve morphogenesis, revealing a new supportive role of the secondary heart field for semilunar valve formation.

Project description:BackgroundThe structure of the valve leaflets and sinuses are crucial in supporting the proper function of the semilunar valve and ensuring leaflet durability. Therefore, an enhanced understanding of the structural characteristics of the semilunar valves is fundamental to the evaluation and staging of semilunar valve pathology, as well as the development of prosthetic or bioprosthetic valves. This paper illustrates the process of combining computer-aided design (CAD), 3D printing and flow assessment with 4-dimensional flow magnetic resonance imaging (MRI) to provide detailed assessment of the structural and hemodynamic characteristics of the normal semilunar valve.MethodsPreviously published geometric data on the aortic valve was used to model the 'normal' tricuspid aortic valve with a CAD software package and 3D printed. An MRI compatible flow pump with the capacity to mimic physiological flows was connected to the phantom. A peak flow rate of 100 mL/s and heart rate of 60 beats per minute were used. MRI measurements included cine imaging, 2D and 4D phase-contrast imaging to assess valve motion, flow velocity and complex flow patterns.ResultsCine MRI data showed normal valve function and competency throughout the cardiac cycle in the 3D-printed phantom. Quantitative analysis of 4D Flow data showed net flow through 2D planes proximal and distal to the valve were very consistent (26.03 mL/s and 26.09 mL/s, respectively). Measurements of net flow value agreed closely with the flow waveform provided to the pump (27.74 mL/s), confirming 4D flow acquisition in relation to the pump output. Peak flow values proximal and distal to the valve were 78.4 mL/s and 63.3 mL/s, respectively. Particle traces of flow from 4D-phase contrast MRI data demonstrated flow through the valve into the ascending aorta and vortices within the aortic sinuses, which are expected during ventricular diastole.ConclusionIn this proof of concept study, we have demonstrated the ability to generate physiological 3D-printed aortic valve phantoms and evaluate their function with cine- and 4D Flow MRI. This technology can work synergistically with promising tissue engineering research to develop optimal aortic valve replacements, which closely reproduces the complex function of the normal aortic valve.

Project description:Congenital heart defects affect ∼2% of live births and often involve malformations of the semilunar (aortic and pulmonic) valves. We previously reported a highly penetrant GATA4 p.Gly296Ser mutation in familial, congenital atrial septal defects and pulmonic valve stenosis and showed that mice harboring the orthologous G295S disease-causing mutation display not only atrial septal defects, but also semilunar valve stenosis. Here, we aimed to characterize the role of Gata4 in semilunar valve development and stenosis using the Gata4G295Ski/wt mouse model. GATA4 is highly expressed in developing valve endothelial and interstitial cells. Echocardiographic examination of Gata4G295Ski/wt mice at 2 months and 1 year of age identified functional semilunar valve stenosis predominantly affecting the aortic valve with distal leaflet thickening and severe extracellular matrix (ECM) disorganization. Examination of the aortic valve at earlier postnatal timepoints demonstrated similar ECM abnormalities consistent with congenital disease. Analysis at embryonic timepoints showed a reduction in aortic valve cushion volume at embryonic day (E)13.5, predominantly affecting the non-coronary cusp (NCC). Although total cusp volume recovered by E15.5, the NCC cusp remained statistically smaller. As endothelial to mesenchymal transition (EMT)-derived cells contribute significantly to the NCC, we performed proximal outflow tract cushion explant assays and found EMT deficits in Gata4G295Ski/wt embryos along with deficits in cell proliferation. RNA-seq analysis of E15.5 outflow tracts of mutant embryos suggested a disease state and identified changes in genes involved in ECM and cell migration as well as dysregulation of Wnt signaling. By utilizing a mouse model harboring a human disease-causing mutation, we demonstrate a novel role for GATA4 in congenital semilunar valve stenosis.This article has an associated First Person interview with the joint first authors of the paper.

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Dual role for CXCL12 signaling in semilunar valve development.

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Dual role for CXCL12 signaling in semilunar valve development.

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