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

Abstract

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 vi- IntroductionThe first wave of embryonic hematopoiesis occurs in the yolk sac from mesodermal precursors at embryonic day 7.0. 1 These early yolk sac mesodermal cells, initially termed hemangioblasts, 2 were thought to have bipotentiality, giving rise to both blood and endothelium. 3 The descendants of hemangioblasts form structures called blood islands, 2 which consist of rounded hematopoietic cells (HCs) circumscribed by an endothelial layer. Although initially thought to propagate the entirety of the adult hematopoietic system, yolk sac hematopoiesis is not fully responsible for definitive hematopoietic stem cell (HSC) emergence but instead provides a transient immature (primitive) hematopoietic population that is later supplanted. [4][5][6] Yet the inability of the yolk sac to produce any definitive adult HCs has recently been questioned. 7,8 In addition, the concept of a mesodermal precursor to HSCs in the early yolk sac has been challenged by recent data suggesting that yolk sac hematopoiesis at the hemangioblast stage occurs through an endothelial intermediate. 9,10 Thus, the yolk sac probably provides both primitive and definitive HCs, but the difference between how the 2 populations emerge and timing of their emergence is still under investigation.Our understanding of intraembryonic definitive hematopoiesis has also been refined by a recent multitude of publications using various systems and model organisms. Previous landmark studies have demonstrated that instead of (or taking into account the more recent data: in addition to) the early yolk sac, later intraembryonic arterial sites give rise to definitive HSCs. [4][5][6][11][12][13] In these sites, large clusters of HSCs are attached to the endothelium, suggesting that a specific subset of endothelial cells (ECs, hemogenic endothelium) 14 are progenitors for HSCs. However, the concept of a mesodermal precursor for HSCs within these intraembryonic sites was also argued. 15,16 The phenomenon of endothelial derivedblood, termed hemogenic endothelium, 9,10,17-21 has become the new paradigm of HSC generation. Vascular...

Progressive maturation toward hematopoietic stem cells in the mouse embryo aorta

“…All IAHC cells express c-kit, but contaminating c-kit 1 cells are also present in the circulating blood and outside of the aorta. 2,15 To circumvent this issue, directlylabeled antibodies against c-kit were injected inside the aorta of nonfixed E10 embryos before AGM dissection/dissociation. Our procedure allows flushing out the blood from the aorta, staining all IAHCs, 10,16 and isolating IAHC cells only ( Figure 1D).…”

VEGFA-dependent and -independent pathways synergise to drive Scl expression and initiate programming of the blood stem cell lineage in Xenopus

“…The LP origin of the DA has been further confirmed by lineage labelling using a HoxB6-Cre line, crossed with a Rosa26 reporter line, that uses the LP enhancer element of HoxB6 (Wasteson et al, 2008). Using this transgenic line, it has been demonstrated that all DA endothelial cells of the mid-gestation embryo and adult mouse derive from LP mesoderm (Wasteson et al, 2008;Zovein et al, 2010). Importantly, it was also determined that virtually the entire bone marrow haematopoietic system derives from the LP (Zovein et al, 2010).…”

“…Using this transgenic line, it has been demonstrated that all DA endothelial cells of the mid-gestation embryo and adult mouse derive from LP mesoderm (Wasteson et al, 2008;Zovein et al, 2010). Importantly, it was also determined that virtually the entire bone marrow haematopoietic system derives from the LP (Zovein et al, 2010). However, neither the exact location of the DA mesodermal precursors in the LP nor their genetic programming is known.…”

The Role of EMT Modulators in Hematopoiesis and Leukemic Transformation

“…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).…”