The heart endocardium is derived from vascular endothelial progenitors

Milgrom-Hoffman, Michal; Harrelson, Zachary; Ferrara, Napoleone; Zelzer, Elazar; Evans, Sylvia M.; Tzahor, Eldad

doi:10.1242/dev.061192

Cited by 120 publications

(123 citation statements)

References 48 publications

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“…Furthermore, BMP expression is sufficient to initiate nfatc1 expression in a subset of vascular endothelial cells in hand2 mutants. These results support a model where endocardial cells are derived from vascular endothelial lineage, in agreement with other recent studies (Bussmann et al, 2007;Schoenebeck et al, 2007;Milgrom-Hoffman et al, 2011).…”

Section: Discussionsupporting

confidence: 93%

“…Endocardial cells and vascular endothelial cells of blood vessels express many of the same molecular markers, which suggests a common origin of both cell types. Indeed, recent evidence argues that endocardial cells are derived from vascular endothelial progenitors (Misfeldt et al, 2009;Milgrom-Hoffman et al, 2011). However, endocardial cells exhibit distinct migratory behavior and express specialized markers such as nfatc1 (de la Pompa et al, 1998), which shows that the endocardial and vascular endothelial cells of blood vessels are biochemically distinct.…”

Section: Introductionmentioning

confidence: 99%

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Myocardium and BMP signaling are required for endocardial differentiation

et al. 2015

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Endocardial and myocardial progenitors originate in distinct regions of the anterior lateral plate mesoderm and migrate to the midline where they coalesce to form the cardiac tube. Endocardial progenitors acquire a molecular identity distinct from other vascular endothelial cells and initiate expression of specific genes such as nfatc1. Yet the molecular pathways and tissue interactions involved in establishing endocardial identity are poorly understood. The endocardium develops in tight association with cardiomyocytes. To test for a potential role of the myocardium in endocardial morphogenesis, we used two different zebrafish models deficient in cardiomyocytes: the hand2 mutant and a myocardial-specific genetic ablation method. We show that in hand2 mutants endocardial progenitors migrate to the midline but fail to assemble into a cardiac cone and do not express markers of differentiated endocardium. Endocardial differentiation defects were rescued by myocardial but not endocardial-specific expression of hand2. In metronidazole-treated myl7:nitroreductase embryos, myocardial cells were targeted for apoptosis, which resulted in the loss of endocardial nfatc1 expression. However, endocardial cells were present and retained expression of general vascular endothelial markers. We further identified bone morphogenetic protein (BMP) as a candidate myocardium-derived signal required for endocardial differentiation. Chemical and genetic inhibition of BMP signaling at the tailbud stage resulted in severe inhibition of endocardial differentiation while there was little effect on myocardial development. Heat-shock-induced bmp2b expression rescued endocardial nfatc1 expression in hand2 mutants and in myocardiumdepleted embryos. Our results indicate that the myocardium is crucial for endocardial morphogenesis and differentiation, and identify BMP as a signal involved in endocardial differentiation.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Myocardium and BMP signaling are required for endocardial differentiation

et al. 2015

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“…By contrast, inactivation of Nkx2-5 by Isl1-Ires-Cre consistently resulted in perinatal (P1) lethality due to OFT septation defects. Both Isl1-Cre and Isl1-Ires-Cre lines mediate early recombination very early in the SHF progenitors (Cai et al, 2003, Yang et al, 2006Sun et al, 2007); however, we found that Isl1-Cre-mediated recombination is far more efficient in the SHF than Isl1-Ires-Cre (Milgrom-Hoffman et al, 2011). Consistent with Isl1-Cre cell lineage studies (supplementary material Fig.…”

Section: Nkx2-5supporting

confidence: 88%

Nkx2-5 regulates cardiac growth through modulation of Wnt signaling by R-spondin3

et al. 2014

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A complex regulatory network of morphogens and transcription factors is essential for normal cardiac development. Nkx2-5 is among the earliest known markers of cardiac mesoderm that is central to the regulatory pathways mediating second heart field (SHF) development. Here, we have examined the specific requirements for Nkx2-5 in the SHF progenitors. We show that Nkx2-5 potentiates Wnt signaling by regulating the expression of the R-spondin3 (Rspo3) gene during cardiogenesis. R-spondins are secreted factors and potent Wnt agonists that in part regulate stem cell proliferation. Our data show that Rspo3 is markedly downregulated in Nkx2-5 mutants and that Rspo3 expression is regulated by Nkx2-5. Conditional inactivation of Rspo3 in the Isl1 lineage resulted in embryonic lethality secondary to impaired development of SHF. More importantly, we find that Wnt signaling is significantly attenuated in Nkx2-5 mutants and that enhancing Wnt/ β-catenin signaling by pharmacological treatment or by transgenic expression of Rspo3 rescues the SHF defects in the conditional Nkx2-5 +/− mutants. We have identified a previously unrecognized genetic link between Nkx2-5 and Wnt signaling that supports continued cardiac growth and proliferation during development. Identification of Rspo3 in cardiac development provides a new paradigm in temporal regulation of Wnt signaling by cardiac-specific transcription factors.

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“…Cardiac contraction and blood flow are intimately associated and cannot be decoupled easily in the developing zebrafish ventricle by genetic means. Although endocardial cells might arise from either vascular endothelial cells or cardiac progenitors, they are a type of endothelial cell and are highly sensitive to flow (Bussmann et al, 2007;Kattman et al, 2006;Milgrom-Hoffman et al, 2011;Moretti et al, 2006;Vermot et al, 2009). We used an in vitro system to apply low-magnitude flow to endothelial cells to model endocardial, cilia-dependent flow responses and found that flow stimulated Notch1, Efnb2 and Nrg1 expression in the absence of myocardially derived factors or circulating factors in the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

et al. 2015

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Congenital heart disease often features structural abnormalities that emerge during development. Accumulating evidence indicates a crucial role for cardiac contraction and the resulting fluid forces in shaping the heart, yet the molecular basis of this function is largely unknown. Using the zebrafish as a model of early heart development, we investigated the role of cardiac contraction in chamber maturation, focusing on the formation of muscular protrusions called trabeculae. By genetic and pharmacological ablation of cardiac contraction, we showed that cardiac contraction is required for trabeculation through its role in regulating notch1b transcription in the ventricular endocardium. We also showed that Notch1 activation induces expression of ephrin b2a (efnb2a) and neuregulin 1 (nrg1) in the endocardium to promote trabeculation and that forced Notch activation in the absence of cardiac contraction rescues efnb2a and nrg1 expression. Using in vitro and in vivo systems, we showed that primary cilia are important mediators of fluid flow to stimulate Notch expression. Together, our findings describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells to regulate cardiac chamber maturation.

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The heart endocardium is derived from vascular endothelial progenitors

Cited by 120 publications

References 48 publications

Myocardium and BMP signaling are required for endocardial differentiation

Myocardium and BMP signaling are required for endocardial differentiation

Nkx2-5 regulates cardiac growth through modulation of Wnt signaling by R-spondin3

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

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