Identification of cardiac hemo-vascular precursors and their requirement of sphingosine-1-phosphate receptor 1 for heart development

Yan Hu,Maria Luisa S Sequeira-Lopez,Minghong Li,Brian C Belyea,R Ariel Gomez,Joachim R Göthert

doi:10.1038/srep45205

Yan Hu, Maria Luisa S Sequeira-Lopez + Show 4 more

Open Access

https://doi.org/10.1038/srep45205

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Abstract

The cardiac endothelium plays a crucial role in the development of a functional heart. However, the precise identification of the endocardial precursors and the mechanisms they require for their role in heart morphogenesis are not well understood. Using in vivo and in vitro cell fate tracing concomitant with specific cell ablation and embryonic heart transplantation studies, we identified a unique set of precursors which possess hemogenic functions and express the stem cell leukemia (SCL) gene driven by its 5′ enhancer. These hemo-vascular precursors give rise to the endocardium, atrioventricular cushions and coronary vascular endothelium. Furthermore, deletion of the sphingosine-1-phosphate receptor 1 (S1P1) in these precursors leads to ventricular non-compaction cardiomyopathy, a poorly understood condition leading to heart failure and early mortality. Thus, we identified a distinctive population of hemo-vascular precursors which require S1P1 to exert their functions and are essential for cardiac morphogenesis.

Highlights

Despite its critical role in heart development, the origin of the cardiac endothelium remains intricate
Using mice with tamoxifen inducible cre recombinase expression driven by either enhancer[13,14], we recently identified in the early embryonic kidney a stem cell leukemia (SCL)+precursor that gives rise to both vascular endothelium and blood cells and requires sphingosine-1-phophate receptor 1 (S1P1) for the development of a normal renal vasculature[15]
S1P1 is predominantly expressed in the endocardium, cardiomyocytes and vascular endothelial cells (ECs) from E8.5, before it is expressed in the vasculature of the head and body which starts at E10.516–18

Summary

Introduction

Despite its critical role in heart development, the origin of the cardiac endothelium remains intricate. The heart possesses two different types of endothelium: the endocardium, a structurally and functionally specialized endothelium, which may originate from both vascular endothelium and multipotent cardiac progenitors[1], and the coronary vascular endothelial cells (CVECs) that seem to develop from endocardium, sinus venous endothelial cells (SVECs) and pro-epicardial precursors[2,3]. Some of these progenitors may possess important hemogenic properties. Using in vivo and in vitro genetic lineage tracings, colony forming assays and a novel crosstransplantation method combined with the inducible and highly specific ablation of SCL+precursors, we tested the hypothesis that those precursors are necessary and require S1P1 for cardiac morphogenesis

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