Endocardial cells are a distinct endothelial lineage derived from Flk1+ multipotent cardiovascular progenitors

Misfeldt, Andrew; Boyle, Scott C.; Tompkins, Kevin L.; Bautch, Victoria L.; Labosky, Patricia A.; Baldwin, H. Scott

doi:10.1016/j.ydbio.2009.06.033

Cited by 113 publications

(123 citation statements)

References 58 publications

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“…Previous analysis of nfatc1 promoter identified a conserved region that contains binding sites for SMAD, which is a known BMP signal transducer (Zhou et al, 2005). BMP has been also implicated in endocardial differentiation in vitro, and in endocardial proliferation during the endocardial ballooning in zebrafish embryos (Misfeldt et al, 2009;Dietrich et al, 2014). However, a BMP requirement for early endocardial differentiation in vivo has not been established.…”

Section: Genetic Ablation Of the Myocardium Results In The Loss Of Enmentioning

confidence: 99%

“…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: Genetic Ablation Of the Myocardium Results In The Loss Of Enmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myocardium and BMP signaling are required for endocardial differentiation

et al. 2015

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“…1GЈ,GЉ). These EYFP + cells are presumably endocardial progenitors (Misfeldt et al, 2009). By contrast, EYFP + cells either weakly expressed or did not express Nkx2-5 (Fig.…”

Section: Expression Analysis Of the Er71-eyfp Reportermentioning

confidence: 90%

ER71 directs mesodermal fate decisions during embryogenesis

et al. 2011

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SUMMARYEr71 mutant embryos are nonviable and lack hematopoietic and endothelial lineages. To further define the functional role for ER71 in cell lineage decisions, we generated genetically modified mouse models. We engineered an Er71-EYFP transgenic mouse model by fusing the 3.9 kb Er71 promoter to the EYFP reporter gene. Using FACS and transcriptional profiling, we examined the EYFP + population of cells in Er71 mutant and wild-type littermates. In the absence of ER71, we observed an increase in the number of EYFP-expressing cells, increased expression of the cardiac molecular program and decreased expression of the hematoendothelial program, as compared with wild-type littermate controls. We also generated a novel Er71-Cre transgenic mouse model using the same 3.9 kb Er71 promoter. Genetic fate-mapping studies revealed that the ER71-expressing cells give rise to the hematopoietic and endothelial lineages in the wild-type background. In the absence of ER71, these cell populations contributed to alternative mesodermal lineages, including the cardiac lineage. To extend these analyses, we used an inducible embryonic stem/embryoid body system and observed that ER71 overexpression repressed cardiogenesis. Together, these studies identify ER71 as a critical regulator of mesodermal fate decisions that acts to specify the hematopoietic and endothelial lineages at the expense of cardiac lineages. This enhances our understanding of the mechanisms that govern mesodermal fate decisions early during embryogenesis.

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“…Although endocardial and endothelial cells share substantial molecular and functional characteristics, a recent study demonstrated molecular and lineage distinctions between these two cell types and suggested that the endocardium and myocardium derive from a common precursor, distinct from endothelial cells (Misfeldt et al, 2009). These previous in vitro studies, and lineage studies of SHF progenitors in mice (Cai et al, 2003;Moretti et al, 2006;Verzi et al, 2005), have given rise to the idea that the endocardium derives from multipotent progenitors within the first and second heart fields (Harris and Black, 2010;Vincent and Buckingham, 2010).…”

Section: Introductionmentioning

confidence: 99%

The heart endocardium is derived from vascular endothelial progenitors

Milgrom-Hoffman

Harrelson

Ferrara³

et al. 2011

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SUMMARYThe embryonic heart is composed of two cell layers: the myocardium, which contributes to cardiac muscle tissue, and the endocardium, which covers the inner lumen of the heart. Whereas significant progress has been made toward elucidating the embryonic origins of the myocardium, the origins of the endocardium remain unclear. Here, we have identified an endocardiumforming field medial to the cardiac crescent, in a continuum with the endothelial plexus. In vivo live imaging of quail embryos revealed that endothelial progenitors, like second/anterior heart field progenitors, migrate to, and enter, the heart from the arterial pole. Furthermore, embryonic endothelial cells implanted into the cardiac crescent contribute to the endocardium, but not to the myocardium. In mouse, lineage analysis focusing on endocardial cells revealed an unexpected heterogeneity in the origins of the endocardium. To gain deeper insight into this heterogeneity, we conditionally ablated Flk1 in distinct cardiovascular progenitor populations; FLK1 is required in vivo for formation of the endocardium in the Mesp1 and Tie2 lineages, but not in the Isl1 lineage. Ablation of Flk1 coupled with lineage analysis in the Isl1 lineage revealed that endothelium-derived Isl1 -endocardial cells were significantly increased, whereas Isl1 + endocardial cells were reduced, suggesting that the endocardium is capable of undergoing regulative compensatory growth. Collectively, our findings demonstrate that the second heart field contains distinct myocardial and endocardial progenitor populations. We suggest that the endocardium derives, at least in part, from vascular endothelial cells.

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Endocardial cells are a distinct endothelial lineage derived from Flk1+ multipotent cardiovascular progenitors

Cited by 113 publications

References 58 publications

Myocardium and BMP signaling are required for endocardial differentiation

Myocardium and BMP signaling are required for endocardial differentiation

ER71 directs mesodermal fate decisions during embryogenesis

The heart endocardium is derived from vascular endothelial progenitors

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