Vascular remodeling of the vitelline artery initiates extravascular emergence of hematopoietic clusters

Department of Molecular, Cellular, and Developmental Biology, University of California at Los Angeles, Los Angeles, CA
Blood (Impact Factor: 10.45). 11/2010; 116(18):3435-44. DOI: 10.1182/blood-2010-04-279497
Source: PubMed


The vitelline artery is a temporary structure that undergoes extensive remodeling during midgestation to eventually become the superior mesenteric artery (also called the cranial mesenteric artery, in the mouse). Here we show that, during this remodeling process, large clusters of hematopoietic progenitors emerge via extravascular budding and form structures that resemble previously described mesenteric blood islands. We demonstrate through fate mapping of vascular endothelium that these mesenteric blood islands are derived from the endothelium of the vitelline artery. We further show that the vitelline arterial endothelium and subsequent blood island structures originate from a lateral plate mesodermal population. Lineage tracing of the lateral plate mesoderm demonstrates contribution to all hemogenic vascular beds in the embryo, and eventually, all hematopoietic cells in the adult. The intraembryonic hematopoietic cell clusters contain viable, proliferative cells that exhibit hematopoietic stem cell markers and are able to further differentiate into myeloid and erythroid lineages. Vitelline artery-derived hematopoietic progenitor clusters appear between embryonic day 10 and embryonic day 10.75 in the caudal half of the midgut mesentery, but by embryonic day 11.0 are sporadically found on the cranial side of the midgut, thus suggesting possible extravascular migration aided by midgut rotation.

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    • "For more than three decades , researchers have repeatedly addressed this question using different technologies. The consensus can be summarized in two points: (1) the earliest blood cell (BC) formation occurs in the extraembryonic region, and (2) the first definitive HSCs that contribute to adult hematopoiesis appearing in the embryo proper and placenta most likely differentiate directly from endothelial cells (ECs) (Cai et al., 2000; Chen et al., 2011; Medvinsky and Dzierzak, 1996; Medvinsky et al., 2011; Ottersbach and Dzierzak, 2005; Rhodes et al., 2008; Zovein et al., 2010). The major point of contention has been how these two events, which occur at different embryonic sites, are related. "
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    ABSTRACT: A large gap exists in our understanding of the course of differentiation from mesoderm to definitive hematopoietic stem cells (HSCs). Previously, we reported that Runx1(+) cells in embryonic day 7.5 (E7.5) embryos contribute to the hemogenic endothelium in the E10.5 aorta-gonad-mesonephros (AGM) region and HSCs in the adult bone marrow. Here, we show that two Runx1(+) populations subdivided by Gata1 expression exist in E7.5 embryos. The hemogenic endothelium and the HSCs are derived only from the Runx1(+)Gata1(-) population. A subset of this population moves from the extra- to intraembryonic region during E7.5-E8.0, where it contributes to the hemogenic endothelium of the dorsal aorta (DA). Migration occurs before the heartbeat is initiated, and it is independent of circulation. This suggests a developmental trajectory from Runx1(+) cells in the E7.5 extraembryonic region to definitive HSCs via the hemogenic endothelium.
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    • "In human ES differentiation, CD34þ cells exist as PDGFRaþ (Davis et al., 2008) supporting the usefulness of PDGFRa to monitor HPC differentiation from ES cells. Some PRaCreER- Etv2KO embryos showed vascular patterning defect in vitelline plexus that is tightly linked to definitive HSC development (Zovein et al., 2010). These results together support the idea that PDGFRa may serve as an additional surface marker to subdivide Flk-1þ cells and enrich useful populations if used in appropriate ES differentiation stages in HPC induction. "
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    ABSTRACT: Background: Early mesoderm can be classified into Flk-1+ or PDGF receptor alpha (PDGFRα)+ population, grossly representing lateral and paraxial mesoderm, respectively. It has been demonstrated that all endothelial (EC) and hematopoietic (HPC) cells are derived from Flk-1+ cells. Although PDGFRα+ cells give rise to ECs/HPCs in in vitro ES differentiation, whether PDGFRα+ population can become hemato-endothelial lineages has not been proved in mouse embryos. Results: Using PDGFRαMerCreMer mice, PDGFRα+ early mesoderm was shown to contribute to endothelial cells including hemogenic ECs, fetal liver B lymphocytes, and Lin-Kit+Sca-1+ (KSL) cells. Contribution of PDGFRα+ mesoderm into ECs and HPCs was limited until E8.5, indicating that PDGFRα+/Flk-1+ population that exists until E8.5 may be the source for hemato-endothelial lineages from PDGFRα+ population. The functional significance of PDGFRα+ mesoderm in vascular development and hematopoiesis was confirmed by genetic deletion of Etv2 or restoration of Runx1 in PDGFRα+ cells. Etv2 deletion and Runx1 restoration in PDGFRα+ cells resulted in abnormal vascular remodeling and rescue of fetal liver CD45+ and Lin-Kit+Sca-1+ (KSL) cells, respectively. Conclusions: Endothelial and hematopoietic cells can be derived from PDGFRα+ early mesoderm in mice. PDGFRα+ mesoderm is functionally significant in vascular development and hematopoiesis from phenotype analysis of genetically modified embryos.
    Full-text · Article · Mar 2013 · Developmental Dynamics
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    • "It was demonstrated through fate mapping that the first HSCs arise as part of the hematopoietic progenitor clusters that emerge from the hemogenic endothelium and subendothelial layers at the ventral part of the dorsal aorta and in the vitelline artery (Rybtsov et al., 2011; Yokomizo et al., 2011). These small cell clusters of hematopoietic progenitors are closely associated with the endothelium and originate from vascular remodelling and extravascular budding (Boisset et al., 2010; Robin et al., 2011; Zovein et al., 2010). This involves changes in endothelial cell shape and loss of cellular adhesion that have been likened to the changes in cell adhesion that epithelial cells undergo during epithelial to mesenchymal transition (EMT). "

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