Three‐dimensional and molecular analysis of the arterial pole of the developing human heart

Sizarov, Aleksander; Lamers, Wouter H.; Mohun, Timothy J.; Brown, Nigel A.; Anderson, Robert H.; Moorman, Antoon F.M.

doi:10.1111/j.1469-7580.2012.01474.x

Cited by 81 publications

(110 citation statements)

References 33 publications

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“…In contrast, the distal outflow tract (dOFT) cushion mesenchyme is largely derived from invading cardiac neural crest cells (NCCs) (Kirby et al 1983; Waldo et al 1998; Jiang et al 2000). Additional cell populations, possibly of second heart field (SHF) origin, may contribute additional mesenchyme to the OFT cushions (Engleka et al 2012; Sizarov et al 2012). …”

Section: Introductionmentioning

confidence: 99%

Endocardial Brg1 disruption illustrates the developmental origins of semilunar valve disease

Akerberg

Sarangam

Stankunas

2015

Developmental Biology

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The formation of intricately organized aortic and pulmonic valves from primitive endocardial cushions of the outflow tract is a remarkable accomplishment of embryonic development. While not always initially pathologic, developmental semilunar valve (SLV) defects, including bicuspid aortic valve, frequently progress to a disease state in adults requiring valve replacement surgery. Disrupted embryonic growth, differentiation, and patterning events that “trigger” SLV disease are coordinated by gene expression changes in endocardial, myocardial, and cushion mesenchymal cells. We explored roles of chromatin regulation in valve gene regulatory networks by conditional inactivation of the Brg1-associated factor (BAF) chromatin remodeling complex in the endocardial lineage. Endocardial Brg1-deficient mouse embryos develop thickened and disorganized SLV cusps that frequently become bicuspid and myxomatous, including in surviving adults. These SLV disease-like phenotypes originate from deficient endocardial-to-mesenchymal transformation (EMT) in the proximal outflow tract (pOFT) cushions. The missing cells are replaced by compensating neural crest or other non-EMT-derived mesenchyme. However, these cells are incompetent to fully pattern the valve interstitium into distinct regions with specialized extracellular matrices. Transcriptomics reveal genes that may promote growth and patterning of SLVs and/or serve as disease-state biomarkers. Mechanistic studies of SLV disease genes should distinguish between disease origins and progression; the latter may reflect secondary responses to a disrupted developmental system.

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Section: Introductionmentioning

confidence: 99%

Endocardial Brg1 disruption illustrates the developmental origins of semilunar valve disease

Akerberg

Sarangam

Stankunas

2015

Developmental Biology

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“…Although significant progress has been made toward elucidating the pathways that drive cardiomyocyte (CM) lineages (reviewed in 1 ), relatively less is known about the origins of the distinct endothelial cell (EC) lineages that constitute the coronary arterial, venous and endocardial compartments of the heart. Cumulative studies from the zebrafish 2,3 , chick 4,5 , mouse 6,7,8 and human 9 models have revealed a heterogeneous origin of the endothelial lineages in the heart, and have recently indicated that a subset of these ECs are derived from a distinct origin of multipotent heart progenitors located in various specific regions of the early heart field 10,11 .…”

Section: Introductionmentioning

confidence: 99%

Driving vascular endothelial cell fate of human multipotent Isl1+ heart progenitors with VEGF modified mRNA

Lui¹,

Zangi

Silva

et al. 2013

Cell Res

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Distinct families of multipotent heart progenitors play a central role in the generation of diverse cardiac, smooth muscle and endothelial cell lineages during mammalian cardiogenesis. The identification of precise paracrine signals that drive the cell-fate decision of these multipotent progenitors, and the development of novel approaches to deliver these signals in vivo, are critical steps towards unlocking their regenerative therapeutic potential. Herein, we have identified a family of human cardiac endothelial intermediates located in outflow tract of the early human fetal hearts (OFT-ECs), characterized by coexpression of Isl1 and CD144/vWF. By comparing angiocrine factors expressed by the human OFT-ECs and non-cardiac ECs, vascular endothelial growth factor (VEGF)-A was identified as the most abundantly expressed factor, and clonal assays documented its ability to drive endothelial specification of human embryonic stem cell (ESC)-derived Isl1+ progenitors in a VEGF receptor-dependent manner. Human Isl1-ECs (endothelial cells differentiated from hESC-derived ISL1+ progenitors) resemble OFT-ECs in terms of expression of the cardiac endothelial progenitor- and endocardial cell-specific genes, confirming their organ specificity. To determine whether VEGF-A might serve as an in vivo cell-fate switch for human ESC-derived Isl1-ECs, we established a novel approach using chemically modified mRNA as a platform for transient, yet highly efficient expression of paracrine factors in cardiovascular progenitors. Overexpression of VEGF-A promotes not only the endothelial specification but also engraftment, proliferation and survival (reduced apoptosis) of the human Isl1+ progenitors in vivo. The large-scale derivation of cardiac-specific human Isl1-ECs from human pluripotent stem cells, coupled with the ability to drive endothelial specification, engraftment, and survival following transplantation, suggest a novel strategy for vascular regeneration in the heart.

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“…The regulation of OFT cushion morphogenesis, size and location remains poorly understood at the molecular level. Certain SHF populations, including those identified by Sizarov et al (Sizarov et al, 2012) and abnormal in morphology and Smad1/5/8 phosphorylation in our models, might play a role in the maintenance of separate nascent truncal lumens close to the OFT wall, perhaps via effects on OFT cushion morphogenesis. As many endocardial /endothelial cells are also recombined by Mef2c[AHF]-Cre , their behavior and signaling may also contribute, especially as cushion shape regulation is sensitive to flow(Colvee and Hurle, 1983; Manner et al, 1993) which might be expected to be abnormal from at least E9 as the right ventricle is abnormally small.…”

Section: Discussionmentioning

confidence: 50%

AcvR1-mediated BMP signaling in second heart field is required for arterial pole development: Implications for myocardial differentiation and regional identity

Thomas

Rajderkar

Lane

et al. 2014

Developmental Biology

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BMP signaling plays an essential role in second heart field-derived heart and arterial trunk development, including myocardial differentiation, right ventricular growth, and interventricular, outflow tract and aortico-pulmonary septation. It is mediated by a number of different BMP ligands, and receptors, many of which are present simultaneously. The mechanisms by which they regulate morphogenetic events and degree of redundancy amongst them have still to be elucidated. We therefore assessed the role of BMP Type I receptor AcvR1 in anterior second heart field-derived cell development, and compared it with that of BmpR1a. By removing Acvr1 using the driver Mef2c[AHF]-Cre, we show that AcvR1 plays an essential role in arterial pole morphogenesis, identifying defects in outflow tract wall and cushion morphology that preceded a spectrum of septation defects from double outlet right ventricle to common arterial trunk in mutants. Its absence caused dysregulation in gene expression important for myocardial differentiation (Isl1, Fgf8) and regional identity (Tbx2, Tbx3, Tbx20, Tgfb2). Although these defects resemble to some degree those in the equivalent Bmpr1a mutant, a novel gene knock-in model in which Bmpr1a was expressed in the Acvr1 locus only partially restored septation in Acvr1 mutants. These data show that both BmpR1a and AcvR1 are needed for normal heart development, in which they play some non-redundant roles, and refine our understanding of the genetic and morphogenetic processes underlying Bmp-mediated heart development important in human congenital heart disease.

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Three‐dimensional and molecular analysis of the arterial pole of the developing human heart

Cited by 81 publications

References 33 publications

Endocardial Brg1 disruption illustrates the developmental origins of semilunar valve disease

Endocardial Brg1 disruption illustrates the developmental origins of semilunar valve disease

Driving vascular endothelial cell fate of human multipotent Isl1+ heart progenitors with VEGF modified mRNA

AcvR1-mediated BMP signaling in second heart field is required for arterial pole development: Implications for myocardial differentiation and regional identity

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