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...

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