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Barone, C.; Azzoni, E.; Orsenigo, R.; , .; Brunelli, S. Hemangioblast and Hemogenic Endothelium. Encyclopedia. Available online: https://encyclopedia.pub/entry/21287 (accessed on 16 July 2025).
Barone C, Azzoni E, Orsenigo R,  , Brunelli S. Hemangioblast and Hemogenic Endothelium. Encyclopedia. Available at: https://encyclopedia.pub/entry/21287. Accessed July 16, 2025.
Barone, Cristiana, Emanuele Azzoni, Roberto Orsenigo,  , Silvia Brunelli. "Hemangioblast and Hemogenic Endothelium" Encyclopedia, https://encyclopedia.pub/entry/21287 (accessed July 16, 2025).
Barone, C., Azzoni, E., Orsenigo, R., , ., & Brunelli, S. (2022, April 01). Hemangioblast and Hemogenic Endothelium. In Encyclopedia. https://encyclopedia.pub/entry/21287
Barone, Cristiana, et al. "Hemangioblast and Hemogenic Endothelium." Encyclopedia. Web. 01 April, 2022.
Hemangioblast and Hemogenic Endothelium
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This entry is adapted from the peer-reviewed paper 10.3390/cells11061061

While hematopoietic stem cells (HSCs) firmly reside at the top of the adult hematopoietic hierarchy, multiple HSC-independent progenitor populations play variegated and fundamental roles during fetal life, which reflect on adult physiology and can lead to disease if subject to perturbations. The importance of obtaining a high-resolution picture of the mechanisms by which the developing embryo establishes a functional hematopoietic system is demonstrated by many recent indications showing that ontogeny is a primary determinant of function of multiple critical cell types.

Hematopoiesis heterogeneity embryo

1. Before the Hemogenic Endothelium: The Hemangioblast Theory

The existence of progenitor cells capable of differentiating into both endothelial and hematopoietic cells (“hemangioblasts”) was initially suggested by Florence Sabin in 1917, based on microscopical observations which noted the close physical proximity of emerging endothelial and red blood cells in the yolk sac (YS) of chicken embryos. The actual “hemangioblast” denomination was coined by Murray in 1932 [1] and referred to a mass of cells derived from the primitive streak mesoderm, containing precursors of endothelium and blood cells. The first experimental data that suggested the presence of a hemangioblast did not arrive until the 1990s when Gordon Keller and colleagues identified a clonal mesodermal precursor for blood and endothelium in embryonic stem (ES) cell differentiation cultures, the blast colony-forming cell (BL-CFC) [2]. This work introduced a paradigm shift in which the hemangioblast no longer represented a population of cells as initially implied by Murray, but a bipotent clonal progenitor for blood and endothelium. The same laboratory went on to provide in vivo evidence of the presence of hemangioblasts in mouse embryos, first detected at the mid-streak stage of gastrulation (E6.75) [3]. Labeling of cells fated to endothelial and hematopoietic lineages in zebrafish was also interpreted as in vivo support for the existence of the hemangioblast [4]. However, in the same years, several experimental evidences started lending support to another theory for the origin of blood cells in the embryo: the hemogenic endothelium (discussed in the following section), which partially clashed with the hemangioblast [5]. After few years, a study based again on ES cultures tried reconciling the two apparently conflicting hypotheses by providing a model in which the hemangioblast gives rise to blood cells through a hemogenic endothelial intermediate [6]. More recent work using lineage tracing of individual cells in the mouse epiblast, primitive streak, and early YS provided little support for the in vivo existence of hemangioblasts as the majority of labeled clones contained either blood or endothelial cells, but very few clones harbored both lineages [7]. These results suggest that precursors for primitive blood and YS endothelium are already specified before gastrulation. Comparison of these lineage tracing data with the BL-CFC model, which was supported primarily by ES cultures, serves as a reminder that in vitro potential does not always equal in vivo fate, which is often more restricted. The hemangioblast may therefore represent the in vitro counterpart of an early mesodermal precursor cell present prior to the commitment to the hematopoietic lineage, as opposed to an actual bipotent progenitor persisting in vivo until midgestation. Further investigation and new experimental approaches are needed to clarify this issue.

2. Heterogeneity of the Hemogenic Endothelium

Several landmark studies in the 1990s provided strong evidence that in vertebrates definitive repopulating HSCs are autonomously generated intra-embryonically within the developing Aorta-Gonad-Mesonephros region (AGM) at midgestation, prior to their appearance in other hematopoietic organs [8][9][10][11][12][13][14]. HSCs and their precursors (pro- and pre-HSCs) are initially found within clusters of hematopoietic cells observed in the aorta and major embryonic arteries [15][16][17][18][19]. Similar to the putative hemangioblasts, these peculiar cell clusters were first identified microscopically in the beginning of the last century, and their close association to the vascular endothelium lent support to the idea that the embryonic endothelium has a hemogenic capacity (reviewed in [20]). Later lineage tracing studies in the chick and mouse models confirmed that this was indeed the case [21][22]. The strongest support for an endothelial origin of hematopoietic cells came from more recent live imaging studies that visualized the transition of endothelium into blood in real-time, both in vitro [23] and in/ex vivo [24][25][26]. The process of endothelial cells acquiring a hematopoietic fate has been termed endothelial-to-hematopoietic transition (EHT). Cells undergoing this process experience major morphological changes independent of cell division, including breakage of tight junctions with adjacent endothelial cells, which result in their acquisition of a round shape and the expression of a hematopoietic program. Importantly, hemogenic endothelial cells are not bipotent but rather already committed to an hematopoietic fate [27][28]. How EHT is regulated at the molecular level is complex and still incompletely understood, though the requirement for the master hematopoietic transcription factor Runx1 is well established (reviewed in [29]). Although EHT has been mostly studied in the context of the dorsal aorta because of it being the primary site of HSC generation, it is now clear that a similar process also takes place in other locations, such as YS, placenta, and possibly other sites [30][31]. Hemogenic endothelium (HE) is inherently transient and it is present only during a limited timeframe in embryonic development, although a potential wave with limited hematopoietic contribution has been described also in the BM of late fetus/young adults [32]. HE represents a common source of various types of stem and progenitor cells generated in multiple anatomical locations at different times during embryogenesis, including progenitors with broad mesodermal potential [33]. This poses an important question: are prospective hematopoietic cells intrinsically fated to become a specific type of stem or progenitor cell already at the HE stage, or do they become specified only later, in response to extrinsic cues from the microenvironment? In other words, when exactly is heterogeneity generated during developmental hematopoiesis? This is a basic research question which carries important translational relevance. Achieving a better understanding of the embryonic hematopoietic system roadmap will inform experimental strategies for production of hematopoietic stem and progenitor cells (HSPCs) ex vivo, which have recently been reported, though their efficiency is still relatively low [34][35].
There is evidence in support of the notion that HE is intrinsically heterogeneous. Clonal assays of individual hemogenic endothelial cells demonstrated very high heterogeneity in their ex vivo output at a given developmental stage [36]. HE could therefore consist of a mix of precursors endowed with distinct potential, and/or that differentiation process proceeds in a highly asynchronous way. These two hypotheses do not exclude each other–and, in fact, there is experimental evidence supporting both. As mentioned above, the formation of HSCs requires the transcription factor Runx1, but also its non-DNA binding partner core binding factor β (CBFβ). The same requirement is observed for the generation of Erythro-Myeloid Progenitors (EMPs), multipotent progenitors distinct and appearing earlier than HSCs. A first demonstration that EMPs and HSCs differentiate from distinct populations of hemogenic endothelial cells came from a study using a CBFβ rescue strategy, which showed that when CBFβ was reintroduced in a null background under the control of two different tissue specific expression transgenes, this caused the alternate rescue of EMPs or HSCs, but not of both [37]. A recent study supported and extended these findings [38]. The authors employed single cell index sorting of HE combined with a co-culture strategy to show that rare HSC-competent HE and the relatively more abundant progenitor-restricted HE can be discriminated by expression of the chemokine receptor CXCRSingle cell RNA-Seq (scRNA-Seq) of the two HE types isolated from E9–E9.5 mouse embryos showed that the HSC competent HE already expresses many of the genes known to be enriched in E11.5 AGM HSCs [38][39]. Accordingly, CXCR4 lineage tracing has been recently used to mark a contribution of intra-but not extra-embryonic HE to innate lymphoid cells [40] and HSC-derived monocytes from microglia and other tissue-resident macrophages (TRM) [41]. Recently, some markers enriched in the YS HE have also been identified, such as Stab2 and Lyve1 [42][43], although the latter was shown not to be exclusively expressed in the YS [44]. These data support the concept that HE cells are already “primed” to become specific types of stem or progenitor cells when they are still undergoing EHT. What are the signals that instruct the generation of heterogeneity in prospective hemogenic endothelial cells?
It is now clear that different signaling pathways are involved in EMP and HSC formation (Table 1). For example, EMP formation from HE in the YS vascular plexus does not require Notch signaling, whereas HSC production is strictly dependent on Notch [45][46][47]. The Notch pathway plays a fundamental role in the arterialization of HE, and the arterial identity of HE is a mandatory condition for the establishment of HSC generation [48][49], but not for EMPs in the YS, as they emerge from both arterial and venous endothelium [31]. The arterial identity of HE appears to be important not only for HSC emergence, but more in general for the appearance of progenitors with lymphoid potential [50]. If the dependence on Notch pathway can be considered a discriminant between HSC-fated HE in the embryo proper and the HE generating EMPs in the YS, the WNT canonical pathway is instead a common regulator of both programs [31]. Other signaling pathways appear to be differentially required in distinct types of HE. In particular, the emergence of HSCs requires mechanistic stimuli provided by the onset of circulation and blood flow, which result in the modulation of several important pathways, among which nitric oxide (NO) [51], cAMP and BMP [52][53], Rho-Yap [54] and metabolic pathways [55]. In contrast, EMP emergence is blood flow-independent [56]. Interestingly, ex vivo modulation of hypoxia/glycolysis yielded opposite effects in embryo proper and YS cells, with a decrease of the hematopoietic output in the former and an increase in the latter [55]. Hepatic leukemia factor (Hlf) is another discriminating factor between EMPs and HSCs [57]. As determined by analysis of a transgenic reporter mouse model, Hlf is expressed by virtually all intra-embryonic c-Kit+ cells, including HE and hematopoietic clusters in the dorsal aorta and vitelline artery, but not by non-hemogenic endothelium and E9.5 YS EMPs. Intriguingly, Hlf appears to be also expressed by some c-Kit clusters in the E10.5 YS. These results are another strong suggestion that the acquisition of the HSC or progenitor fate takes place at an early stage during hematopoietic differentiation.
Table 1. Characteristics of EMP-competent and HSC or lymphoid- competent hemogenic endothelium. A green tick icon indicates dependence on a pathway or expression of a marker. A red cross indicates lack of dependence on a pathway or absence of expression of a marker.
  HSC- and Lymphoid- Competent HE EMP-Competent HE References
Notch pathway dependence Cells 11 01061 i001 Cells 11 01061 i002 [45][46][47]
Arterial identity dependence Cells 11 01061 i001 (Lymphoid potential) Cells 11 01061 i002 [48][49][50]
WNT canonical pathway dependence Cells 11 01061 i001 Cells 11 01061 i001 [31]
Cxcr4 expression Cells 11 01061 i001 (Lymphoid potential) Cells 11 01061 i002 [40]
Lyve1 expression Low Cells 11 01061 i001 [42][43][44]
Hlf expression Cells 11 01061 i001 Cells 11 01061 i002 (until E10.5) [57]
Blood flow dependence Cells 11 01061 i001 Cells 11 01061 i002 [51][52][53][54][55][56]
Hypoxia/glycolysis Decrease of hematopoietic output Increase of hematopoietic output [55]
Many studies have very recently employed scRNA-Seq and newer variants of this technique such as spatial transcriptomics to delve deeper into the study of the molecular determinants of EHT and to gain insight into the cellular and molecular heterogeneity of HE [39][58][59][60][61][62][63][64], mostly in animal models but some also in human [65][66]. These studies mainly focused on intra-embryonic EHT because of its obvious connection with HSC generation, and collectively highlighted how (pro-/pre-)HSC development proceeds in a fairly asynchronous way, with cells at different stages of maturation coexisting in the same embryo. scRNA-seq allowed to describe the differentiation trajectory of EHT in greater detail by revealing previously unrecognized intermediate stages, such as the “pre-HE”, which may represent a developmental bottleneck in which many important molecular pathways are active [58]. Moreover, these studies confirmed the heterogeneity within the intra-aortic clusters population by highlighting the presence of lympho-myeloid biased progenitors, which can be distinguished molecularly [58]; however, the precise cellular relationships between these different progenitor types and the HE are still unclear. Single cell studies not only identified unexpected differences, but also similarities. Indeed, non-HE and HE show surprisingly similar transcriptomes with only a few differentially expressed genes (DEG) [59]; this was confirmed by another study showing that HE cells clustered mainly according to the tissue of origin and to a lesser extent according to hemogenic/non hemogenic identity [67]. In a similar way, clusters in the ventral and dorsal aspects of the aorta also exhibited few global transcriptional differences [59]. Transcriptomics studies have recently been instrumental in identifying microenvironmental cues as driving forces of heterogeneity in the embryonic hematopoietic niche [62][65][68]. These and other studies [69][70][71] showed that secreted factors (BMP, Kit ligand, Noggin as ventral signals; Shh as a dorsal signal are among the most well-characterized) contribute to generating the dorso/ventral polarization of signals that places the embryonic (pre-)HSC niche in the ventral aspect of the aorta.

References

  1. Murray, P.D.F. The development in vitro of the blood of the early chick embryo. Proc. R. Soc. Lond. Ser. B Biol. Sci. 1932, 111, 497–521.
  2. Choi, K.; Kennedy, M.; Kazarov, A.; Papadimitriou, J.C.; Keller, G. A common precursor for hematopoietic and endothelial cells. Development 1998, 125, 725–732.
  3. Huber, T.L.; Kouskoff, V.; Fehling, H.J.; Palis, J.; Keller, G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 2004, 432, 625–630.
  4. Vogeli, K.M.; Jin, S.-W.; Martin, G.R.; Stainier, D.Y.R. A common progenitor for haematopoietic and endothelial lineages in the zebrafish gastrula. Nature 2006, 443, 337–339.
  5. Bollerot, K.; Pouget, C.; Jaffredo, T. The embryonic origins of hematopoietic stem cells: A tale of hemangioblast and hemogenic endothelium. APMIS 2005, 113, 790–803.
  6. Lancrin, C.; Sroczynska, P.; Stephenson, C.; Allen, T.; Kouskoff, V.; Lacaud, G. The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 2009, 457, 892–895.
  7. Padrón-Barthe, L.; Temiño, S.; del Campo, C.V.; Carramolino, L.; Isern, J.; Torres, M. Clonal analysis identifies hemogenic endothelium as the source of the blood-endothelial common lineage in the mouse embryo. Blood 2014, 124, 2523–2532.
  8. Müller, A.M.; Medvinsky, A.; Strouboulis, J.; Grosveld, F.; Dzierzakt, E. Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1994, 1, 291–301.
  9. Cumano, A.; Dieterlen-Lievre, F.; Godin, I. Lymphoid Potential, Probed before Circulation in Mouse, Is Restricted to Caudal Intraembryonic Splanchnopleura. Cell 1996, 86, 907–916.
  10. Garcia-Porrero, J.A.; Godin, I.E.; Dieterlen-Lièvre, F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat. Embryol. 1995, 192, 425–435.
  11. Godin, I.E.; Garcia-Porrero, J.A.; Coutinho, A.; Dieterlen-Lièvre, F.; Marcos, M.A.R. Fran Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors. Nature 1993, 364, 67–70.
  12. Medvinsky, A.; Dzierzak, E. Definitive Hematopoiesis Is Autonomously Initiated by the AGM Region. Cell 1996, 86, 897–906.
  13. Medvinsky, A.L.; Samoylina, N.L.; Müller, A.M.; Dzierzak, E.A.; M, A.M. An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 1993, 364, 64–67.
  14. De Bruijn, M.F.; Speck, N.A.; Peeters, M.C.; Dzierzak, E. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J. 2000, 19, 2465–2474.
  15. Rybtsov, S.; Sobiesiak, M.; Taoudi, S.; Souilhol, C.; Senserrich, J.; Liakhovitskaia, A.; Ivanovs, A.; Frampton, J.; Zhao, S.; Medvinsky, A. Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region. J. Exp. Med. 2011, 208, 1305–1315.
  16. Rybtsov, S.; Batsivari, A.; Bilotkach, K.; Paruzina, D.; Senserrich, J.; Nerushev, O.; Medvinsky, A. Tracing the Origin of the HSC Hierarchy Reveals an SCF-Dependent, IL-3-Independent CD43− Embryonic Precursor. Stem Cell Rep. 2014, 3, 489–501.
  17. Yokomizo, T.; Dzierzak, E. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos. Development 2010, 137, 3651–3661.
  18. Taoudi, S.; Gonneau, C.; Moore, K.; Sheridan, J.M.; Blackburn, C.C.; Taylor, E.; Medvinsky, A. Extensive Hematopoietic Stem Cell Generation in the AGM Region via Maturation of VE-Cadherin+CD45+ Pre-Definitive HSCs. Cell Stem Cell 2008, 3, 99–108.
  19. Gordon-Keylock, S.; Sobiesiak, M.; Rybtsov, S.; Moore, K.; Medvinsky, A. Mouse extraembryonic arterial vessels harbor precursors capable of maturing into definitive HSCs. Blood 2013, 122, 2338–2345.
  20. Swiers, G.; Rode, C.; Azzoni, E.; de Bruijn, M.F. A short history of hemogenic endothelium. Blood Cells Mol. Dis. 2013, 51, 206–212.
  21. Jaffredo, T.; Gautier, R.; Eichmann, A.; Dieterlen-Lièvre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 1998, 125, 4575–4583.
  22. Zovein, A.C.; Hofmann, J.J.; Lynch, M.; French, W.J.; Turlo, K.A.; Yang, Y.; Becker, M.S.; Zanetta, L.; Dejana, E.; Gasson, J.C.; et al. Fate Tracing Reveals the Endothelial Origin of Hematopoietic Stem Cells. Cell Stem Cell 2008, 3, 625–636.
  23. Eilken, H.M.; Nishikawa, S.-I.; Schroeder, T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 2009, 457, 896–900.
  24. Bertrand, J.Y.; Chi, N.C.; Santoso, B.; Teng, S.; Stainier, D.Y.; Traver, D. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 2010, 464, 108–111.
  25. Boisset, J.-C.; Van Cappellen, W.; Andrieu-Soler, C.; Galjart, N.; Dzierzak, E.; Robin, C. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 2010, 464, 116–120.
  26. Kissa, K.; Herbomel, P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 2010, 464, 112–115.
  27. Ditadi, A.; Sturgeon, C.M.; Tober, J.; Awong, G.; Kennedy, M.; Yzaguirre, A.D.; Azzola, L.; Ng, E.S.; Stanley, E.G.; French, D.L.; et al. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat. Cell Biol. 2015, 17, 580–591.
  28. Swiers, G.; Baumann, C.; O’Rourke, J.; Giannoulatou, E.; Taylor, S.; Joshi, A.; Moignard, V.; Pina, C.; Bee, T.; Kokkaliaris, K.D.; et al. Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level. Nat. Commun. 2013, 4, 2924.
  29. Ottersbach, K. Endothelial-to-haematopoietic transition: An update on the process of making blood. Biochem. Soc. Trans. 2019, 47, 591–601.
  30. Yzaguirre, A.D.; Speck, N.A. Insights into blood cell formation from hemogenic endothelium in lesser-known anatomic sites. Dev. Dyn. 2016, 245, 1011–1028.
  31. Frame, J.M.; Fegan, K.H.; Conway, S.J.; McGrath, K.E.; Palis, J. Definitive Hematopoiesis in the Yolk Sac Emerges from Wnt-Responsive Hemogenic Endothelium Independently of Circulation and Arterial Identity. Stem Cells 2015, 34, 431–444.
  32. Yvernogeau, L.; Gautier, R.; Petit, L.; Khoury, H.; Relaix, F.; Ribes, V.; Sang, H.; Charbord, P.; Souyri, M.; Robin, C.; et al. In vivo generation of haematopoietic stem/progenitor cells from bone marrow-derived haemogenic endothelium. Nat. Cell Biol. 2019, 21, 1334–1345.
  33. Azzoni, E.; Conti, V.; Campana, L.; Dellavalle, A.; Adams, R.H.; Cossu, G.; Brunelli, S. Hemogenic endothelium generates mesoangioblasts that contribute to several mesodermal lineages in vivo. Development 2014, 141, 1821–1834.
  34. Sugimura, R.; Jha, D.K.; Han, A.; Soria-Valles, C.; da Rocha, E.L.; Lu, Y.-F.; Goettel, J.A.; Serrao, E.; Rowe, R.G.; Malleshaiah, M.; et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 2017, 545, 432–438.
  35. Lis, R.; Karrasch, C.C.; Poulos, M.G.; Kunar, B.; Redmond, D.; Duran, J.G.B.; Badwe, C.R.; Schachterle, W.; Ginsberg, M.; Xiang, J.; et al. Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature 2017, 545, 439–445.
  36. Ganuza, M.; Hadland, B.; Chabot, A.; Li, C.; Kang, G.; Bernstein, I.; McKinney-Freeman, S. Murine hemogenic endothelial precursors display heterogeneous hematopoietic potential ex vivo. Exp. Hematol. 2017, 51, 25–35.e6.
  37. Chen, M.J.; Li, Y.; De Obaldia, M.E.; Yang, Q.; Yzaguirre, A.D.; Yamada-Inagawa, T.; Vink, C.S.; Bhandoola, A.; Dzierzak, E.; Speck, N.A. Erythroid/Myeloid Progenitors and Hematopoietic Stem Cells Originate from Distinct Populations of Endothelial Cells. Cell Stem Cell 2011, 9, 541–552.
  38. Dignum, T.; Varnum-Finney, B.; Srivatsan, S.R.; Dozono, S.; Waltner, O.; Heck, A.M.; Ishida, T.; Nourigat-McKay, C.; Jackson, D.L.; Rafii, S.; et al. Multipotent progenitors and hematopoietic stem cells arise independently from hemogenic endothelium in the mouse embryo. Cell Rep. 2021, 36, 109675.
  39. Vink, C.S.; Calero-Nieto, F.J.; Wang, X.; Maglitto, A.; Mariani, S.A.; Jawaid, W.; Gottgens, B.; Dzierzak, E. Iterative Sin-gle-Cell Analyses Define the Transcriptome of the First Functional Hematopoietic Stem Cells. Cell Rep. 2020, 31, 107627.
  40. Simic, M.; Manosalva, I.; Spinelli, L.; Gentek, R.; Shayan, R.R.; Siret, C.; Girard-Madoux, M.; Wang, S.; de Fabritus, L.; Verschoor, J.; et al. Distinct Waves from the Hemogenic Endothelium Give Rise to Layered Lymphoid Tissue Inducer Cell Ontogeny. Cell Rep. 2020, 32, 108004.
  41. Werner, Y.; Mass, E.; Kumar, P.A.; Ulas, T.; Händlers, K.; Horne, A.; Klee, K.; Lupp, A.; Schütz, D.; Saaber, F.; et al. Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke. Nat. Neurosci. 2020, 23, 351–362.
  42. Li, Y.-Q.; Gong, Y.; Hou, S.; Huang, T.; Wang, H.; Liu, D.; Ni, Y.; Wang, C.; Wang, J.; Hou, J.; et al. Spatiotemporal and Functional Heterogeneity of Hematopoietic Stem Cell-Competent Hemogenic Endothelial Cells in Mouse Embryos. Front. Cell Dev. Biol. 2021, 9, 699263.
  43. Lee, L.K.; Ghorbanian, Y.; Wang, W.; Wang, Y.; Kim, Y.J.; Weissman, I.L.; Inlay, M.A.; Mikkola, H.K. LYVE1 Marks the Divergence of Yolk Sac Definitive Hemogenic Endothelium from the Primitive Erythroid Lineage. Cell Rep. 2016, 17, 2286–2298.
  44. Ganuza, M.; Chabot, A.; Tang, X.; Bi, W.; Natarajan, S.; Carter, R.; Gawad, C.; Kang, G.; Cheng, Y.; McKinney-Freeman, S. Murine hematopoietic stem cell activity is derived from pre-circulation embryos but not yolk sacs. Nat. Commun. 2018, 9, 5405.
  45. Bertrand, J.Y.; Cisson, J.L.; Stachura, D.L.; Traver, D. Notch signaling distinguishes 2 waves of definitive hematopoiesis in the zebrafish embryo. Blood 2010, 115, 2777–2783.
  46. Hadland, B.K.; Huppert, S.S.; Kanungo, J.; Xue, Y.; Jiang, R.; Gridley, T.; Conlon, R.A.; Cheng, A.M.; Kopan, R.; Longmore, G.D. A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood 2004, 104, 3097–3105.
  47. Kumano, K.; Chiba, S.; Kunisato, A.; Sata, M.; Saito, T.; Nakagami-Yamaguchi, E.; Yamaguchi, T.; Masuda, S.; Shimizu, K.; Takahashi, T.; et al. Notch1 but Not Notch2 Is Essential for Generating Hematopoietic Stem Cells from Endothelial Cells. Immunity 2003, 18, 699–711.
  48. Uenishi, G.I.; Jung, H.S.; Kumar, A.; Park, M.A.; Hadland, B.K.; McLeod, E.; Raymond, M.; Moskvin, O.; Zimmerman, C.E.; Theisen, D.J.; et al. NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells. Nat. Commun. 2018, 9, 1828.
  49. Bonkhofer, F.; Rispoli, R.; Pinheiro, P.; Krecsmarik, M.; Schneider-Swales, J.; Tsang, I.H.C.; De Bruijn, M.; Monteiro, R.; Peterkin, T.; Patient, R. Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium. Nat. Commun. 2019, 10, 3577.
  50. Park, M.A.; Kumar, A.; Jung, H.S.; Uenishi, G.; Moskvin, O.V.; Thomson, J.A.; Slukvin, I.I. Activation of the Arterial Program Drives Development of Definitive Hemogenic Endothelium with Lymphoid Potential. Cell Rep. 2018, 23, 2467–2481.
  51. North, T.E.; Goessling, W.; Peeters, M.; Li, P.; Ceol, C.; Lord, A.M.; Weber, G.J.; Harris, J.; Cutting, C.C.; Huang, P.; et al. Hematopoietic Stem Cell Development Is Dependent on Blood Flow. Cell 2009, 137, 736–748.
  52. Diaz, M.F.; Li, N.; Lee, H.J.; Adamo, L.; Evans, S.M.; Willey, H.E.; Arora, N.; Torisawa, Y.S.; Vickers, D.A.; Morris, S.A.; et al. Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. J. Exp. Med. 2015, 212, 665–680.
  53. Kim, P.G.; Nakano, H.; Das, P.P.; Chen, M.J.; Rowe, R.G.; Chou, S.S.; Ross, S.J.; Sakamoto, K.M.; Zon, L.I.; Schlaeger, T.M.; et al. Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence. J. Exp. Med. 2015, 212, 633–648.
  54. Lundin, V.; Sugden, W.W.; Theodore, L.N.; Sousa, P.M.; Han, A.; Chou, S.; Wrighton, P.J.; Cox, A.G.; Ingber, D.E.; Goessling, W.; et al. YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow. Dev. Cell 2020, 52, 446–460.e5.
  55. Azzoni, E.; Frontera, V.; Anselmi, G.; Rode, C.; James, C.; Deltcheva, E.M.; Demian, A.S.; Brown, J.; Barone, C.; Patelli, A.; et al. The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition. Cell Rep. 2021, 37, 110103.
  56. Lux, C.T.; Yoshimoto, M.; McGrath, K.; Conway, S.J.; Palis, J.; Yoder, M.C. All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood 2008, 111, 3435–3438.
  57. Yokomizo, T.; Watanabe, N.; Umemoto, T.; Matsuo, J.; Harai, R.; Kihara, Y.; Nakamura, E.; Tada, N.; Sato, T.; Takaku, T.; et al. Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors. J. Exp. Med. 2019, 216, 1599–1614.
  58. Zhu, Q.; Gao, P.; Tober, J.; Bennett, L.; Chen, C.; Uzun, Y.; Li, Y.; Howell, E.D.; Mumau, M.; Yu, W.; et al. Developmental trajectory of prehematopoietic stem cell formation from endothelium. Blood 2020, 136, 845–856.
  59. Baron, C.S.; Kester, L.; Klaus, A.; Boisset, J.-C.; Thambyrajah, R.; Yvernogeau, L.; Kouskoff, V.; Lacaud, G.; Van Oudenaarden, A.; Robin, C. Single-cell transcriptomics reveal the dynamic of haematopoietic stem cell production in the aorta. Nat. Commun. 2018, 9, 2517.
  60. Fadlullah, M.Z.H.; Neo, W.H.; Lie-A-Ling, M.; Thambyrajah, R.; Patel, R.; Mevel, R.; Aksoy, I.; Khoa, N.D.; Savatier, P.; Fontenille, L.; et al. Murine AGM single-cell profiling identifies a continuum of hemogenic endothelium differentiation marked by ACE. Blood 2022, 139, 343–356.
  61. Oatley, M.; Bölükbası, Ö.V.; Svensson, V.; Shvartsman, M.; Ganter, K.; Zirngibl, K.; Pavlovich, P.V.; Milchevskaya, V.; Foteva, V.; Natarajan, K.N.; et al. Single-cell transcriptomics identifies CD44 as a marker and regulator of endothelial to haematopoietic transition. Nat. Commun. 2020, 11, 586.
  62. Yvernogeau, L.; Klaus, A.; Maas, J.; Morin-Poulard, I.; Weijts, B.; Schulte-Merker, S.; Berezikov, E.; Junker, J.P.; Robin, C. Multispecies RNA tomography reveals regulators of hematopoietic stem cell birth in the embryonic aorta. Blood 2020, 136, 831–844.
  63. Weijts, B.; Yvernogeau, L.; Robin, C. Recent Advances in Developmental Hematopoiesis: Diving Deeper With New Technologies. Front. Immunol. 2021, 12, 790379.
  64. Hou, S.; Li, Z.; Zheng, X.; Gao, Y.; Dong, J.; Ni, Y.; Wang, X.; Li, Y.; Ding, X.; Chang, Z.; et al. Embryonic endothelial evolution towards first hematopoietic stem cells revealed by single-cell transcriptomic and functional analyses. Cell Res. 2020, 30, 376–392.
  65. Crosse, E.I.; Gordon-Keylock, S.; Rybtsov, S.; Binagui-Casas, A.; Felchle, H.; Nnadi, N.C.; Kirschner, K.; Chandra, T.; Tamagno, S.; Webb, D.J.; et al. Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development. Cell Stem Cell 2020, 27, 822–839.e8.
  66. Zeng, Y.; He, J.; Bai, Z.; Li, Z.; Gong, Y.; Liu, C.; Ni, Y.; Du, J.; Ma, C.; Bian, L.; et al. Tracing the first hematopoietic stem cell generation in human embryo by single-cell RNA sequencing. Cell Res. 2019, 29, 881–894.
  67. Gao, L.; Tober, J.; Gao, P.; Chen, C.; Tan, K.; Speck, N.A. RUNX1 and the endothelial origin of blood. Exp. Hematol. 2018, 68, 2–9.
  68. McGarvey, A.; Rybtsov, S.; Souilhol, C.; Tamagno, S.; Rice, R.; Hills, D.; Godwin, D.; Rice, D.; Tomlinson, S.R.; Medvinsky, A. A molecular roadmap of the AGM region reveals BMPER as a novel regulator of HSC maturation. J. Exp. Med. 2017, 214, 3731–3751.
  69. Souilhol, C.; Gonneau, C.; Lendinez, J.G.; Batsivari, A.; Rybtsov, S.; Wilson, H.; Morgado-Palacin, L.; Hills, D.; Taoudi, S.; Antonchuk, J.; et al. Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells. Nat. Commun. 2016, 7, 10784.
  70. Azzoni, E.; Frontera, V.; E McGrath, K.; Harman, J.; Carrelha, J.; Nerlov, C.; Palis, J.; Jacobsen, S.E.W.; De Bruijn, M.F. Kit ligand has a critical role in mouse yolk sac and aorta–gonad–mesonephros hematopoiesis. EMBO Rep. 2018, 19.
  71. Mirshekar-Syahkal, B.; Fitch, S.R.; Ottersbach, K. Concise Review: From Greenhouse to Garden: The Changing Soil of the Hematopoietic Stem Cell Microenvironment During Development. Stem Cells 2014, 32, 1691–1700.
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Subjects: Developmental Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Cristiana Barone
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Emanuele Azzoni
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Roberto Orsenigo
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Silvia Brunelli
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Update Date: 06 Apr 2022
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