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  • Thus it is worth mentioning

    2018-10-22

    Thus, it is worth mentioning that none of these aforementioned studies undoubtedly provide a definitive answer concerning the potential origin of HSCs in the mouse embryo. To add to the complexity, it is possible, as shown in the Xenopus embryo (Turpen et al., 1997) and suggested in mouse (Matsuoka et al., 2001), that both YS and P-Sp have intrinsic HSC potential, but that the in vivo microenvironment would define the fate of HSC precursor cells. Despite uncertainty on the anatomical origin of HSCs, much work has been performed to understand what cell type developmentally precedes HSCs.
    Cellular origin of hematopoietic stem cells: The hemogenic endothelium The observation of both a temporal and spatial localization of blood and endothelial cells in the YS blood islands led to the concept of the hemangioblast, a common precursor for hematopoietic and endothelial cells (Sabin, 1920). Since then, there has been genetic and functional evidence for this concept. For example, Flk-1 deficient embryos lack blood and endothelium (Shalaby et al., 1995). Likewise, Flk1−/− ESCs fail to contribute to blood and endothelial lineages in chimeras, suggesting the existence of Flk1+ hemangioblast cells (Shalaby et al., 1997). In chickens, mesodermal cells expressing the Flk1 homologue can differentiate clonally either into endothelial or hematopoietic lineages in the presence or absence of VEGF (Eichmann et al., 1997). Also, the blast colony-forming cells (BL-CFC), identified during mouse ESC differentiation, are able to generate cells of both endothelial and hematopoietic lineages (Choi et al., 1998). Such bipotential precursors, most likely corresponding to the hemangioblast, can be detected in gastrulating mouse embryos (Huber et al., 2004). They arise in the primitive streak before migrating to the YS, where they will differentiate in vivo into hematopoietic and endothelial cells (Huber et al., 2004; Vogeli et al., 2006). The hemangioblast usually refers to the bipotential precursor at the origin of early YS hematopoiesis (Huber, 2010). However, a strikingly close connection between endothelial and hematopoietic cells can also be observed later on, in the main intra-embryonic vessels (the dorsal Leupeptin Supplier and the umbilical and vitelline arteries) (Dantschakoff, 1909; Dieterlen-Lievre et al., 2006; Yokomizo and Dzierzak, 2010). There, hematopoietic cells are often seen grouped together in clusters of cells (Intra-Aortic Hematopoietic Clusters, IAHCs), tightly attached to the endothelial layer of the vessels. This close association between endothelium and hematopoietic cells has led to the hypothesis in the early 20th century that specialized endothelial cells, termed hemogenic, would have the ability to give rise to hematopoietic cells (Dantschakoff, 1909; Jordan, 1917). The presence of IAHCs has been described in many vertebrate species (Dieterlen-Lievre et al., 2006). Decades later, it was also shown by immunostaining on fixed embryo sections that IAHCs express both hematopoietic and endothelial markers, again emphasizing the close developmental relationship between the two cell lineages (Garcia-Porrero et al., 1998). IAHCs, due to their morphologic and phenotypic characteristics, are presumed to contain hematopoietic stem and progenitor cells (Dieterlen-Lievre and Martin, 1981). This is now, in part, confirmed since mice deficient for the transcription factor Runx1, that do not have any HSCs or progenitors, are also devoid of IAHCs (embryos die around E11.5) (Okuda et al., 1996; Wang et al., 1996; Cai et al., 2000; North et al., 1999). In addition, HSCs and IAHC cells co-express similar HSC markers (e.g. c-kit) and endothelial markers (e.g. CD31, VE-cadherin, CD34) at E11.5. The hypothesized endothelial origin of IAHCs (and therefore of the putative HSCs) was first tested in the avian model. Pre-IAHC stage embryos received injections directly into the heart with Ac-DiI-LDL (endothelial cells specifically uptake this molecule) and were examined 24h later. Newly formed IAHCs were found to express the pan-hematopoietic marker CD45 while still retaining the Ac-DiI-LDL staining (Jaffredo et al., 1998, 2000). Such experiments therefore proved the endothelial origin of the newly formed hematopoietic cells. Such specialized endothelial cells capable of generating hematopoietic cells are referred to as hemogenic. Similar lineage tracing experiments were also performed in the mouse embryo and gave a similar conclusion (Sugiyama et al., 2003). The transition from endothelial cells to hematopoietic cells is now well known in the chicken embryo (Fig. 2). The ventral endothelial cells become thicker, start to express CD45 and form IAHCs. The endothelial floor is progressively replaced by endothelial cells of somitic origin that are no longer hemogenic (Pouget et al., 2006). Such a process regulates the aortic hematopoietic production both in time and space. In mice, an alternative hypothesis has been proposed based on the observation of a cell population located in the sub-aortic mesenchyme that expresses hematopoietic markers (Bertrand et al., 2005). According to this hypothesis, HSC precursors would migrate through the endothelium (without taking any characteristics of the endothelium) and bud into the lumen of the aorta to form IAHCs.