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Haematopoietic stem cells (HSCs) emerge from the haemogenic endothelium (HE) localised in the ventral wall of the embryonic dorsal aorta (DA). The HE generates HSCs through a process known as the endothelial to haematopoietic transition (EHT), which has been visualised in live embryos and is currently under intense study. However, EHT is the culmination of multiple programming events, which are as yet poorly understood, that take place before the specification of HE. A number of haematopoietic precursor cells have been described before the emergence of definitive HSCs, but only one haematovascular progenitor, the definitive haemangioblast (DH), gives rise to the DA, HE and HSCs. DHs emerge in the lateral plate mesoderm (LPM) and have a distinct origin and genetic programme compared to other, previously described haematovascular progenitors. Although DHs have so far only been established in Xenopus embryos, evidence for their existence in the LPM of mouse and chicken embryos is discussed here. We also review the current knowledge of the origins, lineage relationships, genetic programming and differentiation of the DHs that leads to the generation of HSCs. Importantly, we discuss the significance of the gene regulatory network (GRN) that controls the programming of DHs, a better understanding of which may aid in the establishment of protocols for the de novo generation of HSCs in vitro.
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27531714
???displayArticle.link???FEBS Lett ???displayArticle.grants???[+]
Fig. 1. Haematopoietic stem cells derive from the lateral plate mesoderm. (A) Xenopus diploidâtriploid chimeras showing that adult blood derives from the trunk. Very few, if any, cells derive from the head. Chimeras were generated at stage 22 of development. Thy, thymic blood;
Spl, splenic blood; RBC, red blood cells. Data after Maeno et al. [27]. (B) Dorsal, not ventral, tissues within the trunk give rise to adult blood. Diploid tissues were grafted into triploid recipients and their contribution to thymocytes (open bars) and red blood cells (closed bars) were
analysed throughout development. Dorsal- derived blood increased as the ventral- derived contribution decreased. Grafting experiments were performed at stage 22 of development. D, dorsal; V, ventral. Figure after Maeno et al. [4] (C) HSCs derive from the LPM immediately posterior to the pronephros (PN) and alongside the Wolffian duct (WD)
Fig. 2. The lateral plate mesoderm contains definitive haemangioblasts (DHs). (A) Expression of Fli1 in a transverse section of a stage 26 Xenopus embryo, showing the localisation of DHs within the LPM. No morphological differences are noticeable with surrounding cells. Dorsal is to the top. s, somites; n, notochord; e, endoderm. (B) In situ hybridisation showing that Tal1/Scl-expressing DHs localise dorsal to the Wolffian duct anlagen, indicated by Lhx1 expression. Dorsal is to the top. (C) Diagram showing that DHs localise ventral to the somites and dorsal to the Wolffian duct (WD). (D) The emergence of DHs in association with the somites and WD is conserved through evolution. Although the exact location of DHs is only known in Xenopus embryos, Tal1/Scl expression in the LPM (shown in red) of other systems is associated with the somites and WD (shown in green). Red bars in the chick and mouse embryos show the localisation of emerging precursors of the DA, which have been shown to express Tal1/Scl [40,47].
Fig. 3. Fate map in Xenopus embryos indicates AP patterning of the endothelium. (A) Localisation of the germ layers in the 32-cell stage embryo. Haematopoietic and endothelial cells emerge from the mesodermal layer. AP, animal pole; VP, vegetal pole. (B) The 32-cell stage fate map of the dorsal aorta (DA) and other axial vessels shows an AP regionalisation of the vasculature. The contribution of blastomeres of the 32-cell stage embryo to the vasculature are outlined on an embryo stained for expression of the vascular gene, AA4. Anterior to the right and dorsal to the top. PCV, posterior cardinal vein. (C) Time course of blastomere C3 contribution to haematopoietic tissues. Blastomere C3 gives rise to the dorsal LPM at stage 26 and to the DA and HSCs at stage 43 [23]. During gastrulation, C3 derivatives are distinctly localised from the progenitors of embryonic blood in the DMZ and VMZ. Sections show LacZ staining from one of the two C3 blastomeres at two axial levels: at the level of the bifurcated DA (Anterior) and at the level of the medial DA in the trunk (Posterior). C3 contributes to the entire DA of the trunk and, anteriorly, to the bifurcated DA proximal to the trunk. PN, pronephros; n, notochord; WD, Wolffian duct.
Fig. 4. Haematovascular progenitors within the LPM are regionalised. (A) Comparison of Kdr/Flk1, Tal1/Scl and Pax8 expression in the dorsal LPM of stage 26 Xenopus embryos showing three regions according to their association with the developing pronephric system: an anterior region associated with the pronephros (PN), a middle region associated with the Wolffian duct, and a posterior region without any association with the pronephric system. Transplantation experiments have shown that HSCs derive from the middle region of the LPM. However, further analysis is required to establish whether the anterior and posterior LPM give rise to any HSCs. (B) Regionalisation of the LPM in 10-somite zebrafish embryos. Scl expression, shown in red, subdivides the LPM into anterior and posterior. The posterior LPM localises alongside the Wolffian duct (shown in green) and can be further subdivided into vascular precursors which do not express Gata1, a region proximal to the cloaca which gives rise to the posterior blood island and a middle region which gives rise to embryonic blood. This middle region is also thought to contain HSC precursors. (C) Runx1 expression (red) in the DA of the 30hpf zebrafish embryo localises in the trunk. This region has been shown to undergo EHT to give rise to HSCs. The area expressing Runx1 spans the Wolffian duct (green), is posterior to the pronephros (PN) and does not extend posterior to the yolk extension. Thus, emergence of HSCs appears to be restricted to the trunk.
Fig. 5. HSCs emerge in the single medial DA of the trunk and the bifurcated DA proximal to it. (A) Runx1 expression in the Xenopus DA is restricted to the trunk and encompasses the WDs. This suggests that HE only emerges in the trunk. (B) At the time when sprouting of intra-aortic haematopoietic clusters is observed, Runx1 expression is confined to the trunk and also extends anteriorly to the bifurcated DA, suggesting that HSCs may emerge in these vessels too. (C) Functional assays in the mouse have demonstrated that HSCs emerge in the single medial DA of the trunk as well as in the bifurcated DA proximal to it [80].
