How to Make a Heart Valve: From Embryonic Development to Bioengineering of Living Valve Substitutes

MacGrogan, Donal; Luxán, Guillermo; Driessen-Mol, Anita Anita; Bouten, Cvc Carlijn; Baaijens, Fpt Frank; Pompa, José Luis de la

doi:10.1101/cshperspect.a013912

Cited by 68 publications

(58 citation statements)

References 198 publications

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“…Heart valve development in the mouse begins at E9.5-10.5 with the formation of cardiac cushions at the sites of future atrioventricular (AVC) and outflow tract (OFT) valves (Gitler et al, 2003; MacGrogan et al, 2014). Cushion formation begins with endocardial-mesenchymal transformation (EMT), a process in which endocardial cells delaminate from an organized cell layer, transform into mesenchymal cells, and invade the matrix that separates the endocardial and myocardial cell layers (Markwald et al, 1977).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to their contribution to future valves, cardiac cushions also form the membranous septum and basal parts of the aortic and pulmonic outflow tracts. Following completion of EMT, the bulky cardiac cushions are gradually remodeled to mature valves with thin, perfectly co-apting leaflets (MacGrogan et al, 2014). Although the processes of EMT and cushion formation have been elucidated in significant molecular and cellular detail (reviewed in (von Gise and Pu, 2012)), the mechanisms that underlie subsequent remodeling to mature valves remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

et al. 2017

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Summary Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development, and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

et al. 2017

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“…In mouse embryos, development of the AVC valves begins at embryonic day E9.5, when endocardial cells undergo an endothelial to mesenchymal transition (EndMT or EMT) in response to signals from the myocardium. The delaminating endocardial cells migrate into the cardiac jelly and give rise to the cardiac cushion mesenchyme, which are then remodeled into the mature valve structures (MacGrogan et al, 2014). The EMT in the AVC is controlled by BMP2 signaling from the myocardium, which synergizes with myocardial TGFβ2 and endocardial NOTCH signaling to activate downstream effectors that include the Snai1 transcriptional regulator (Luna-Zurita et al, 2010; Ma et al, 2005; Niessen et al, 2008; Timmerman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development

et al. 2017

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Summary The HAND2 transcriptional regulator controls cardiac development and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted and we combined ChIP-Seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.

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“…First, the cushion fields are specified by Notch and BMP signaling to generate specialized myocardium that produces EMT-inducing ligands and a correspondingly responsive endocardium (Timmerman et al, 2004;Luna-Zurita et al, 2010;Sugi et al, 2004;Ma et al, 2005;Wang et al, 2005;McCulley et al, 2008). TGF-β and other factors then induce changes in endocardial gene expression programs that repress epithelial-state determinants and upregulate mesenchymal factors that promote ECM invasion and cell migration (reviewed by MacGrogan et al, 2014). The canonical Wnt signaling pathway, involving transcriptional changes driven by stabilized nuclear β-catenin and TCF/Lef transcription factors, might also directly promote EMT (Liebner et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin signaling enables developmental transitions during valvulogenesis

et al. 2016

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Heart valve development proceeds through coordinated steps by which endocardial cushions (ECs) form thin, elongated and stratified valves. Wnt signaling and its canonical effector β-catenin are proposed to contribute to endocardial-to-mesenchymal transformation (EMT) through postnatal steps of valvulogenesis. However, genetic redundancy and lethality have made it challenging to define specific roles of the canonical Wnt pathway at different stages of valve formation. We developed a transgenic mouse system that provides spatiotemporal inhibition of Wnt/β-catenin signaling by chemically inducible overexpression of Dkk1. Unexpectedly, this approach indicates canonical Wnt signaling is required for EMT in the proximal outflow tract (pOFT) but not atrioventricular canal (AVC) cushions. Furthermore, Wnt indirectly promotes pOFT EMT through its earlier activity in neighboring myocardial cells or their progenitors. Subsequently, Wnt/β-catenin signaling is activated in cushion mesenchymal cells where it supports FGF-driven expansion of ECs and then AVC valve extracellular matrix patterning. Mice lacking Axin2, a negative Wnt regulator, have larger valves, suggesting that accumulating Axin2 in maturing valves represents negative feedback that restrains tissue overgrowth rather than simply reporting Wnt activity. Disruption of these Wnt/β-catenin signaling roles that enable developmental transitions during valvulogenesis could account for common congenital valve defects.

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How to Make a Heart Valve: From Embryonic Development to Bioengineering of Living Valve Substitutes

Cited by 68 publications

References 198 publications

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development

Wnt/β-catenin signaling enables developmental transitions during valvulogenesis

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