Muscularization of the Mesenchymal Outlet Septum during Cardiac Development

Hoff, Maurice J.B. van den; Wessels, Andy

doi:10.3390/jcdd7040051

Cited by 8 publications

(16 citation statements)

References 79 publications

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“…ACTG1 encodes a major constituent protein of the contractile apparatus; and S100A11 encodes a calcium-binding protein. These properties suggest that cells in this cluster are cardiomyofibroblasts, developing mainly in the outflow tract (OFT CMs), where ventricular muscle as well as semilunar valves and the great arteries develop (Boukens et al, 2009;van den Hoff et al, 2001;Sahara et al, 2019).…”

Section: Cmsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted March 1, 2022. ; https://doi.org/10.1101/2022.02.26.482029 doi: bioRxiv preprint pathways. These differences suggest that the larger cluster (3) is related to the primordial atria, developing mainly into the trabeculated atrial appendages (atrial trabecular CMs) while cluster 5 is related to the central smooth-walled part of the atria developing from the epicardium and mesenchyme and large veins, including the pulmonary veins (Douglas et al, 2009;Gallego et al, 1997;van den Hoff et al, 2001) (atrial conduit CMs). The GO terms of SAN CMs (Figure 2B) were related to conduction, regulation of action potential, and heart rate.…”

Section: Atrial Cardiomyocyte Typesmentioning

confidence: 99%

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High cardiomyocyte diversity in human early prenatal heart development

Sylvén

Wärdell

Månsson‐Broberg

et al. 2022

Preprint

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Cardiomyocytes play key roles during cardiogenesis, but have poorly understood features, especially in prenatal stages. Thus, we have characterized human prenatal cardiomyocytes, 6.5–7 weeks post-conception, in detail by integrating single–cell RNA sequencing, spatial transcriptomics, and ligand–receptor interaction information. Using a computational workflow developed to dissect cell type heterogeneity, localize cell types, and explore their molecular interactions, we identified eight types of developing cardiomyocyte, more than double compared to the ones identified in the Human Developmental Cell Atlas. These have high variability in cell cycle activity, mitochondrial content, and connexin gene expression, and are differentially distributed in the ventricles, including outflow tract, and atria, including sinoatrial node. Moreover, cardiomyocyte ligand–receptor crosstalk is mainly with non–cardiomyocyte cell types, encompassing cardiogenesis-related pathways. Thus, early prenatal human cardiomyocytes are highly heterogeneous and develop unique location–dependent properties, with complex ligand–receptor crosstalk. Further elucidation of their developmental dynamics may give rise to new therapies.

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Section: Cmsmentioning

confidence: 99%

Section: Atrial Cardiomyocyte Typesmentioning

confidence: 99%

High cardiomyocyte diversity in human early prenatal heart development

Sylvén

Wärdell

Månsson‐Broberg

et al. 2022

Preprint

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“…Given the importance of TGFβ2 myocardialization [ 23 ], this study provided direct evidence of a role of myocardial TGFβ2 in the muscularization of the AV septum. Since Tgfb2 myocardial CKO embryos exhibit AV cushion fusion and septal abnormalities, it is difficult to determine a precise role of myocardial TGFβ2 in the myocardialization of AV cushions.…”

Section: Discussionmentioning

confidence: 71%

“…In mice, the systemic loss of TGFβ2 leads to embryonic valvular defects such as dysmorphic and abnormally thickened mitral valves and myocardial defects [ 13 , 20 ]. TGFβ2 is myogenic and Tgfb2 −/− exhibit spongy myocardium along with other compaction defects such as a thin outer layer of the ventricular myocardium as well as the impaired myocardialization of the atrioventricular (AV) cushions [ 21 , 22 , 23 ]. Despite such severe cardiac defects in TGFβ2 germline knockout fetuses, to date date, there are no studies done on the specific developmental role of myocardium-derived TGFβ2.…”

Section: Introductionmentioning

confidence: 99%

Myocardial TGFβ2 Is Required for Atrioventricular Cushion Remodeling and Myocardial Development

Bhattacharya

Al-Sammarraie

Gebere

et al. 2021

JCDD

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Among the three transforming growth factor beta (TGFβ) ligands, TGFβ2 is essential for heart development and is produced by multiple cell types, including myocardium. Heterozygous mutations in TGFB2 in patients of connective tissue disorders result in congenital heart defects and adult valve malformations, including mitral valve prolapse (MVP) with or without regurgitation. Tgfb2 germline knockout fetuses exhibit multiple cardiac defects but the role of myocardial-TGFβ2 in heart development is yet to be elucidated. Here, myocardial Tgfb2 conditional knockout (CKO) embryos were generated by crossing Tgfb2flox mice with Tgfb2+/−; cTntCre mice. Tgfb2flox/− embryos were normal, viable. Cell fate mapping was done using dual-fluorescent mT/mG+/− mice. Cre-mediated Tgfb2 deletion was assessed by genomic PCR. RNAscope in situ hybridization was used to detect the loss of myocardial Tgfb2 expression. Histological, morphometric, immunohistochemical, and in situ hybridization analyses of CKOs and littermate controls at different stages of heart development (E12.5–E18.5) were used to determine the role of myocardium-derived TGFβ2 in atrioventricular (AV) cushion remodeling and myocardial development. CKOs exhibit a thin ventricular myocardium, AV cushion remodeling defects and developed incomplete AV septation defects. The loss of myocardial Tgfb2 resulted in impaired cushion maturation and dysregulated cell death. Phosphorylated SMAD2, a surrogate for TGFβ signaling, was “paradoxically” increased in both AV cushion mesenchyme and ventricular myocardium in the CKOs. Our results indicate that TGFβ2 produced by cardiomyocytes acting as cells autonomously on myocardium and via paracrine signaling on AV cushions are required for heart development.

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“…Multiple signal pathways affect the development of mouse endocardial cushion, like TGF-β/BMP, Notch, ErbB, Wnt/catenin, and VEGF 32, 33, 34, 35 . We first compared the RNA expression of EndMT signals of the myocardium between E9.5 WT and KO heart AV cushion tissues via RT-qPCR.…”

Section: Resultsmentioning

confidence: 99%

ERp44 is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium

Yang

Jin

et al. 2021

Preprint

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Rationale: Endocardial cushions are precursors of the valvoseptal complex that separates the four heart chambers and control blood flow through the heart. Abnormalities in endocardial cushion development lead to atrioventricular septal defects (AVSDs), which affect 1 in 2,100 live births. Several genes have been implicated in the development of endocardial cushions. Specifically, endoplasmic reticulum-resident protein 44 (ERp44) has been found to play a role in the early secretory pathway, but its function in heart development has not been well studied. Objective: The goal of this study was to investigate the role of ERp44 in heart development in mice. Approach and Results: Using conventional and tissue-specific knockout mouse models, we demonstrated that ERp44 plays a specific role in heart development. ERp44 knockout (KO) mice were smaller in size, and most mice died during early postnatal life. KO hearts exhibited the typical phenotypes of congenital heart diseases, such as abnormal heart shapes as well as severe septal and valvular defects. Similar phenotypes were found in cTnt-cre+/-; Erp44fl/fl mice, which indicated that myocardial ERp44 principally controls endocardial cushion formation. Further studies demonstrated that the deletion of ERp44 significantly decreased the proliferation of cushion cells and impaired the endocardial-mesenchymal transition (EndMT), which was followed by endocardial cushion dysplasia. Finally, we found that ERp44 directly bound to VEGFA and controlled its release. Conclusions: ERp44 contributes to the development of the endocardial cushion by affecting the EndMT of cushion cells by regulating VEGFA release in myocardial cells.

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Muscularization of the Mesenchymal Outlet Septum during Cardiac Development

Cited by 8 publications

References 79 publications

High cardiomyocyte diversity in human early prenatal heart development

High cardiomyocyte diversity in human early prenatal heart development

Myocardial TGFβ2 Is Required for Atrioventricular Cushion Remodeling and Myocardial Development

ERp44 is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium

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