Progressive maturation toward hematopoietic stem cells in the mouse embryo aorta

Abstract

Key Points• Intraaortic clusters contain pre-HSCs progressively maturing toward an HSC fate.Clusters of cells attached to the endothelium of the main embryonic arteries were first observed a century ago. Present in most vertebrate species, such clusters, or intraaortic hematopoietic clusters (IAHCs), derive from specialized hemogenic endothelial cells and contain the first few hematopoietic stem cells (HSCs) generated during embryonic development. However, some discrepancies remained concerning the spatio-temporal appearance and the numbers of IAHCs and HSCs. Therefore, the exact cell composition and function of IAHCs remain unclear to date. We show here that IAHCs contain pre-HSCs (or HSC precursors) that can mature into HSCs in vivo (as shown by the successful long-term multilineage reconstitution of primary neonates and secondary adult recipients). Such IAHC pre-HSCs could contribute to the HSC pool increase observed at midgestation. The novel insights in pre-HSC to HSC transition represent an important step toward generating transplantable HSCs in vitro that are needed for autologous HSC transplantation therapies. (Blood. 2015;125(3):465-469)

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

“…Our results indicate that Chd1 drives an elevated transcriptional output that is specifically required for survival and expansion of HSPCs emerging from the endothelium. There are about 400-500 Kit + cells in the dorsal aorta at E10.5 (7), and only a subset of these are HSPCs (42,51). The fact that HSPCs arise from such a rare fraction of the endothelium and need to rapidly give rise to the entire definitive blood system is expected to generate a high demand for cellular growth pathways, including transcription and translation.…”

Developing HSCs become Notch independent by the end of maturation in the AGM region

“…Pro-HSCs (VC ) which are mainly present at E11.5. [24][25][26][27][28][29] In contrast to dHSCs, these precursors are not detectable by direct transplantations into adult irradiated recipients. A maturation step in an embryonic or neonatal environment is needed to allow them to develop into transplantable dHSCs.…”

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

“…Aortic endothelium transdifferentiates into HSCs via an endothelial-to-hematopoietic transition (EHT) (Chen et al, 2009;Jaffredo et al, 1998;Zovein et al, 2008), a process that is conserved across vertebrates (Bertrand et al, 2010;Boisset et al, 2014Boisset et al, , 2010Chen et al, 2009;Jaffredo et al, 2000Jaffredo et al, , 1998Kissa and Herbomel, 2010;Lam et al, 2010). EHT produces hematopoietic stem and progenitor cells (HSPCs) that rapidly enter circulation in zebrafish (Bertrand et al, 2010;Boisset et al, 2010;Kissa and Herbomel, 2010;Lam et al, 2010) or proliferate and differentiate locally to form hematopoietic clusters in the chick and mammalian embryo (Boisset et al, 2014;Jaffredo et al, 2000;North et al, 2002;Tavian et al, 1999;Yokomizo and Dzierzak, 2010). Nascent HSPCs home to the caudal hematopoietic tissue (CHT) of zebrafish and to the placenta and fetal liver in mammals, where they undergo proliferation and maturation.…”