Abstract
SummaryHematopoietic stem cells (HSCs) are self-renewing multipotent stem cells that generate mature blood lineages throughout life. They, together with hematopoietic progenitor cells (collectively known as HSPCs), emerge from hemogenic endothelium in the floor of the embryonic dorsal aorta by an endothelial-to-hematopoietic transition (EHT). Here we demonstrate that transforming growth factor β (TGFβ) is required for HSPC specification and that it regulates the expression of the Notch ligand Jagged1a in endothelial cells prior to EHT, in a striking parallel with the epithelial-to-mesenchymal transition (EMT). The requirement for TGFβ is two fold and sequential: autocrine via Tgfβ1a and Tgfβ1b produced in the endothelial cells themselves, followed by a paracrine input of Tgfβ3 from the notochord, suggesting that the former programs the hemogenic endothelium and the latter drives EHT. Our findings have important implications for the generation of HSPCs from pluripotent cells in vitro.
Highlights
Hematopoietic stem cells (HSCs) are specified during embryonic development from a subset of arterial endothelial cells located in the floor of the dorsal aorta (DA)
transforming growth factor b (TGFb) Signaling Components Are Expressed in or around the Embryonic Site of HSC Emergence To investigate whether TGFb signaling could play a role in hematopoietic stem and progenitor cells (HSPCs) specification in zebrafish, we first carried out expression analysis. tgfbR2 is expressed in the head vasculature and in the somites at 15 hpf and in the DA and the somites from at least 18 hpf up to 24 hpf (Figures 1A and S1A), prior to the onset of runx1 expression in the hemogenic endothelium (HE) (Wilkinson et al, 2009)
TGFb ligands are expressed in the region at the onset of HE formation: tgfb1a and tgfb1b are expressed in the endothelium, including the DA at 15 hpf, 24 hpf, and 27 hpf (Figures 1B, 1C, S1B, and S1C)
Summary
Hematopoietic stem cells (HSCs) are specified during embryonic development from a subset of arterial endothelial cells located in the floor of the dorsal aorta (DA). HSCs emerge by a process termed the endothelial-to-hematopoietic transition (EHT) (Bertrand et al, 2010; Boisset et al, 2010; Kissa and Herbomel, 2010). The Notch receptor Notch is the main driver of HSPC emergence from HE, likely downstream of its ligand Jagged (Gama-Norton et al, 2015; Hadland et al, 2015; Jang et al, 2015) and is thought to drive runx expression via Gata (Robert-Moreno et al, 2005). Jagged is dispensable for arterial programming but required in the endothelium for the specification of HSPCs (Espin-Palazon et al, 2014; Gama-Norton et al, 2015; Robert-Moreno et al, 2008)
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