Fate Tracing Reveals the Endothelial Origin of Hematopoietic Stem Cells

Abstract

Summary Hematopoietic stem cells (HSCs) originate within the aorta-gonado-mesonephros (AGM) region of the midgestation embryo, but the cell type responsible for their emergence is unknown since critical hematopoietic factors are expressed in both the AGM endothelium and its underlying mesenchyme. Here we employ a temporally restricted genetic tracing strategy to selectively label the endothelium, and separately its underlying mesenchyme, during AGM development. Lineage tracing endothelium, via an inducible VE-cadherin Cre line, reveals that the endothelium is capable of HSC emergence. The endothelial progeny migrate to the fetal liver, and later to the bone marrow, are capable of expansion, self-renewal, and multi-lineage hematopoietic differentiation. HSC capacity is exclusively endothelial, as ex vivo analyses demonstrate lack of VE-cadherin Cre induction in circulating and fetal liver hematopoietic populations. Moreover, AGM mesenchyme, as selectively traced via a myocardin Cre line, is incapable of hematopoiesis. Our genetic tracing strategy therefore reveals an endothelial origin of HSCs.

A short history of hemogenic endothelium

“…However, hematopoietic cell clusters that protrude from the endothelium have been observed not only here, but also in other hemogenic sites, including the vitelline and umbilical arteries, yolk sac, and placenta [23,26,[61][62][63]. Lineage tracing indicates that EHT also occurs in those tissues [27,28,64]. All this brings to mind the suggestion made 100 years ago, that hemogenic activity is an inherent property of all young, undifferentiated embryonic endothelium [22,23,62].…”

“…The first in vivo experimental support came much later, from lineage tracing of endothelium in the chick embryo [25,26]. More recently, lineage-tracing studies in which Cre recombinase was expressed under the regulatory control of the endothelial marker VE-Cadherin (VECadh) lent further support to this model [27,28]. Arguably, the strongest support for an endothelial origin of hematopoietic cells came from the recent time-lapse imaging studies that visualized the transition of endothelium into blood in real-time, both in vitro [29] and in/ex vivo [30][31][32][33].…”

Definitive human and mouse hematopoiesis originates from the embryonic endothelium: a new class of HSCs based on VE-cadherin expression

“…In the mouse, candidate ECs sorted from the yolk sac and embryonic aorta-gonad-mesonephros (AGM) region formed blood cells in culture (Nishikawa et al, 1998b, Fraser et al, 2002. Recently, several lineage-marking systems have been developed to directly approach the question of the temporal and spatial origin of blood cells in situ (Chen et al, 2009;Zovein et al, 2008;Li et al, 2006;De Bruijn et al, 2002;North et al, 2002). All these approaches have suggested that discrete subsets of vascular ECs transiently exhibit blood-forming potential during vertebrate development.…”

“…Several reports suggest that intaembryonic HSCs are generated by other structures, called subaortic patches (SAPs), located below the aortic floor, and which appear as another supportive niche for the intraembryonic HSCs generation in the paraaortic splanchnopleura (PSp)/AGM region (Bertrand et al, 2005;Manaia et al, 2000). At the end, it is possible that both origins exist (Zovein et al, 2008), and that depending on the site of production, HSCs might be endowed with different properties in adult life.…”

Origine endothéliale des cellules souches hématopoïétiques

“…Ce remodelage de l'endothélium aortique permet ainsi de contrôler la production hématopoïétique dans le temps et l'espace. [24]. Une autre stratégie utilise l'inactivation de Runx1 (facteur de transcription crucial pour la production des CSH) dans les cellules exprimant la VE-cadhérine, ce qui bloque la production des CSH.…”