Aorta-gonad-mesonephros

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The aorta-gonad-mesonephros (AGM) [1] [2] [3] [4] [5] is a region of embryonic mesoderm that develops during embryonic development from the para-aortic splanchnopleura in chick, [6] mouse [4] [5] and human [7] embryos. The very first adult definitive haematopoietic stem cells, capable of long-term multilineage repopulation of adult irradiated recipients, originate from the ventral endothelial wall of the embryonic dorsal aorta, [8] [9] through an endothelial transdifferentiation process referred to as an 'endothelial-to-haematopoietic transition' (EHT). [10] [11] [12] [13] [14] In the mouse embryo, these very first HSCs are characterised by their expression of Ly6A-GFP [8] [15] (Sca1), CD31, [16] [15] CD34, [17] cKit, [16] [17] CD27, [16] CD41, [18] Gata2, [16] [19] [13] Runx1, [20] [21] Notch1, [22] and BMP [23] amongst others.

Contents

The aorta-gonad-mesonephros (AGM) region is an area derived from splanchnopleura mesoderm identified in embryonic humans, mice, and non-mammalian vertebrates such as birds and zebrafish. It contains the dorsal aorta, genital ridges and mesonephros and lies between the notochord and the somatic mesoderm, extending from the umbilicus to the anterior limb bud of the embryo. [24] The AGM region plays an important role in embryonic development, being the first autonomous intra-embryonic site for definitive haematopoiesis. [3] [2] [5] [25] [26] Definitive haematopoiesis produces haematopoietic stem cells that have the capacity to 'self-renew' when serially transplanted into irradiated recipients, and differentiate into any of the blood cell lineages of the adult haematopoietic hierarchy. [5] [25] Specialised endothelial cells in the floor of the dorsal aorta (within the AGM region), identified as haemogenic endothelium, differentiate into haematopoietic stem cells.

In embryonic development

The AGM region is derived from the mesoderm layer of the embryo. During organogenesis (around the fourth week in human embryos), the visceral region of the mesoderm, the splanchnopleura, transforms into distinct structures consisting of the dorsal aorta, genital ridges and mesonephros. [27] For a period during embryonic development, the dorsal aorta produces hematopoietic stem cells, which will eventually colonise the liver and give rise to all mature blood lineages in the adult. [28] By birth, the dorsal aorta becomes the descending aorta, while the genital ridges form the gonads. [28] The mesonephros go on to form nephrons and other associated structures of the kidneys.

The formation of the AGM region has been best described in non-mammalian vertebrates such as Xenopus laevis. Shortly after gastrulation, cells from the dorsolateral plate, analogous to the splanchnopleura mesoderm in mammals, migrate to the midline, beneath the notochord to form the dorsal aorta, and laterally the cardinal veins and nephric ducts. [29]

Function

The most significant function of the aorta gonad mesonephros region is its role in definitive haematopoiesis. Definitive haematopoiesis is the second wave of embryonic haematopoiesis and give rise to all hematopoietic stem cells in the adult hematopoietic system. The aorta gonad mesonephros region has been shown to harbour multipotent hematopoietic colony-forming unit-spleen (CFU-S) progenitor cells [1] and pluripotential long-term repopulating hematopoietic stem cells (LTR-HSCs). [2] [3] In contrast to the yolk sac, the extra-embryonic haematopoietic site, the number of CFU-S was much greater in the aorta gonad mesonephros region. LTR-HSC activity was also found in the aorta gonad mesonephros region at a slightly earlier time than in the yolk sac and fetal liver. Thus indicating the potency of definitive haematopoiesis from this region. Furthermore, isolated organ cultures of the AGM from mouse embryos can autonomously initiate hematopoietic stem cell activity, without influence from the yolk sac or liver. [3] At 10 days post coitus (d.p.c.) the aorta gonad mesonephros region was able to initiate and expand definitive haematopoietic stem cell activity, whereas no haematopoietic activity was seen in the yolk sac until 11 d.p.c. This is the same in human embryos, where they are first detected at day 27 in the aorta gonad mesonephros region, expand rapidly at day 35, then disappear at day 40. This “disappearance” correlates to the migration of these hematopoietic stem cells to the foetal liver, where it becomes the subsequent site of haematopoiesis.

Histology

The dorsal aorta consists of an endothelial layer and an underlying stromal layer. There is also another cell population called haematogenic endothelium, which derive from the endothelial layer to produce hematopoietic stem cells.

Endothelial cells

Endothelial cells line the lumen of all blood vessels as a single squamous endothelial layer. These cells maintain contact with each other through tight junctions. In the AGM, endothelial cells line the lumen of the dorsal aorta. A specialised subset of endothelial cells, haemogenic endothelium has the potential to differentiate into haematopoietic stem cells.

Haemogenic endothelium

Hematopoietic stem cells (HSC) were detected adhering firmly to the ventral endothelium of the dorsal aorta. These cells have been identified to originate from haematogenic endothelium, a precursor of both hematopoietic and endothelial lineages. This is where HSC differentiate from the endothelial lining of the dorsa aorta. VE-cadherin, a specific marker for endothelial cells is found on the luminal side of the aortic endothelium. Cells clustered on the wall of the dorsal aorta also expressed VE-cadherin as well as CD34, a common hematopoietic and endothelial marker; and CD45, a marker present on hematopoietic cells. When these special endothelial cells were cultured in vitro, they were able to generate haematopoietic stem cells at a higher rate than cells from a haematopoietic origin. Thus the co-expression of cell surface markers from both lineages suggests that hematopoietic stem cells differentiate from endothelial cells of the dorsal aorta in the AGM.

Time lapse imaging of live zebrafish embryos has provided the visualisation of haematogenic endothelium differentiating into hematopoietic stem cells. From about 30 hours post-fertilization, a few hours before the first appearance of dHSCs, many endothelial cells from the aortic floor start contracting and bending towards the subaortic space, usually lasting for 1–2 hours. Then these cells undergo a further contraction along the mediolateral axis, bringing together its two lateral endothelial neighbours and releasing its contact with them. The emerged cell assumes a rounded morphology and maintains strong contacts with the rostral and caudal endothelial cells to travel along the vessel’s axis. Electron microscope images show that these cells maintain contacts through tight junctions. Once these contacts dissolve, the cell, due to its apical-base polarity, moves into the subaortic space and consequently colonises other hematopoietic organs.

Haematopoietic stem cell development

In the AGM production of HSCs, it is believed that haemogenic endothelial cells play a key role. Haemogenic endothelial cells are specific endothelial cells that concurrently express both haematopoietic and endothelial markers. These haemogenic endothelial cells then become activated, releasing their binding with adjacent endothelial cells, and entering circulation in a process referred to as ‘budding’. This occurs at E9.5 in the developing mouse embryo. From here the haemogenic endothelial cells develop into HSCs. However, the precise signalling pathway involved in haemogenic endothelial cell activation is unknown, but several signalling molecules have been implicated including nitric oxide (NO), Notch 1, and Runx1.

Signaling pathways involved in AGM haemogenic endothelial cell activation include:

Runx1

RUNX1 (also known as AML1) is a transcription factor that has been heavily implicated in the production and activation of haemogenic endothelial cells in the AGM. RUNX1 knockout studies have shown a complete removal of definitive haematopoietic activity in all foetal tissues before embryo lethality at E12. RUNX1 knockouts also produce morphological changes in the AGM, with excessive crowding of mesenchymal cells. As mesenchymal cells differentiate into endothelial cells, the absence of RUNX1 may impact on the ability of mesenchymal cells to differentiate into haemogenic endothelial cells. This would explain the increase in mesenchymal cell number, and the distinct lack of cells positive for other haematopoietic markers. Runx1 has also been implicated in the activation of haemogenic endothelium. Using conditional knockouts it was shown that the removal of Runx1 expression in AGM haemogenic endothelial cells, prevented the production of HSCs. The same experiments also showed that once HSCs were produced, Runx1 was no longer required producing no deviation in HSC activity compared to controls. Additionally, when AGM cells from Runx1 knockouts underwent retroviral transfer in vitro to overexpress Runx1, they were able to be rescued and produce definitive haematopoietic cells. This suggests that Runx1 plays a critical role in the signalling pathway for haemogenic cell activation and its production from mesenchymal cells.

Nitric oxide

Nitric oxide signalling has also been shown to play a role in haemogenic endothelial cell production and activation, possibly by regulating the expression of Runx1. The sheer stress from blood flow activates mechanoreceptors in the blood vessel to produce NO, making NO production circulation dependent. This is seen in Ncx1 knockouts, where the failure to develop a heartbeat, and consequent lack of circulation results in a down-regulation of Runx1 and no haematopoietic activity in the AGM. When Ncx1 knockouts are supplied with an external source of NO, haematopoietic activity in the AGM returns to near wild-type levels. This isolates NO signalling as the key factor controlling haematopoiesis, and not just the presence of circulation. However the signalling cascade linking NO to Runx1 expression is yet to be elucidated. NO signalling has also been shown to control the motility of endothelial cells by regulating the expression of cell adhesion molecules ICAM-1. This makes it likely that it is involved in the budding of haemogenic endothelial cells into circulation. As Runx1 is also crucial for haemogenic endothelial cell activation, it is possible that NO regulates both of these downstream effects.

Notch signaling

Notch1 is another protein which has been implicated in the signalling pathway for HSC production. Notch1 knockouts exhibit normal haematopoiesis in the yolk sac, but fail to produce any HSCs in the AGM. Experiments have been shown that decreased Notch1 expression also affects the expression of Runx1, resulting in its downregulation. Further experiments in which Notch1 is overexpressed shows large clusters of definitive haematopoietic cells developing in the endothelium of the AGM. As Runx1 expression is proportional to haematopoietic cell production, these results suggest that Notch1 is also involved in regulating Runx1.

Related Research Articles

Haematopoiesis Formation of blood cellular components

Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation.

Germ cell

A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo meiosis, followed by cellular differentiation into mature gametes, either eggs or sperm. Unlike animals, plants do not have germ cells designated in early development. Instead, germ cells can arise from somatic cells in the adult, such as the floral meristem of flowering plants.

Hematopoietic stem cell Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

CD34 Cluster of differentiation protocol that identifies cell surface antigens.

CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.

Cell therapy Therapy in which cellular material is injected into a patient

Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.

Adult stem cell Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

Extramedullary hematopoiesis medical condition

Extramedullary hematopoiesis refers to hematopoiesis occurring outside of the medulla of the bone. It can be physiologic or pathologic.

Hemangioblasts are the multipotent precursor cells that can differentiate into both hematopoietic and endothelial cells. In the mouse embryo, the emergence of blood islands in the yolk sac at embryonic day 7 marks the onset of hematopoiesis. From these blood islands, the hematopoietic cells and vasculature are formed shortly after. Hemangioblasts are the progenitors that form the blood islands. To date, the hemangioblast has been identified in human, mouse and zebrafish embryos.

Intermediate mesoderm

Intermediate mesoderm or intermediate mesenchyme is a narrow section of the mesoderm located between the paraxial mesoderm and the lateral plate of the developing embryo. The intermediate mesoderm develops into vital parts of the urogenital system, as well as the reproductive system.

Endothelial stem cell Stem cell in bone marrow that gives rise to endothelial cells

Endothelial stem cells (ESCs) are one of three types of stem cells found in bone marrow. They are multipotent, which describes the ability to give rise to many cell types, whereas a pluripotent stem cell can give rise to all types. ESCs have the characteristic properties of a stem cell: self-renewal and differentiation. These parent stem cells, ESCs, give rise to progenitor cells, which are intermediate stem cells that lose potency. Progenitor stem cells are committed to differentiating along a particular cell developmental pathway. ESCs will eventually produce endothelial cells (ECs), which create the thin-walled endothelium that lines the inner surface of blood vessels and lymphatic vessels. The lymphatic vessels include things such as arteries and veins. Endothelial cells can be found throughout the whole vascular system and they also play a vital role in the movement of white blood cells

CD27

CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.

RUNX1

Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.

Sean J. Morrison

Sean J. Morrison is a Canadian-American stem cell biologist and cancer researcher. Morrison is the director of Children's Medical Center Research Institute at UT Southwestern, a nonprofit research institute established in 2011 as a joint venture between Children’s Health System of Texas and UT Southwestern Medical Center. The CRI was established in 2011 by Morrison with the mission to perform transformative biomedical research at the interface of stem cell biology, cancer, and metabolism to better understand the biological basis of disease. He is a Howard Hughes Medical Institute Investigator and member of the National Academy of Medicine. From 2015 to 2016 Morrison served as the president of the International Society for Stem Cell Research.

KLF2

Krüppel-like Factor 2 (KLF2), also known as lung Krüppel-like Factor (LKLF), is a protein that in humans is encoded by the KLF2 gene on chromosome 19. It is a member of the Krüppel-like factor family of zinc finger transcription factors, and it has been implicated in a variety of biochemical processes in the human body, including lung development, embryonic erythropoiesis, epithelial integrity, T-cell viability, and adipogenesis.

HHEX

Hematopoietically-expressed homeobox protein HHEX is a protein that in humans is encoded by the HHEX gene and also known as Proline Rich Homeodomain protein PRH.

CFU-Meg is a colony forming unit. Haematopoiesis in the bone marrow starts off from a haematopoietic stem cell (HSC) and this can differentiate into the myeloid and lymphoid cell lineages. In order to eventually produce a megakaryocyte, the haematopoietic stem cell must generate myeloid cells, so it becomes a common myeloid progenitor, CFU-GEMM. This in turn develops into CFU-Meg, which is the colony forming unit that leads to the production of megakaryocytes.

Hemogenic endothelium is a special subset of endothelial cells scattered within blood vessels that can differentiate into haematopoietic cells.

Haematopoietic system

The haematopoietic system is the system in the body involved in the creation of the cells of blood.

Many human blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the hematopoietic stem cell (HSC). As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis. This event requires a special environment, termed the hematopoietic stem cell niche, which provides the protection and signals necessary to carry out the differentiation of cells from HSC progenitors. This niche relocates from the yolk sac to eventually rest in the bone marrow of mammals. Many pathological states can arise from disturbances in this niche environment, highlighting its importance in maintaining hematopoiesis.

Since haematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them in a microscope. Therefore, there are many techniques to isolate haematopoietic stem cells (HSCs). HSCs can be identified or isolated by the use of flow cytometry where the combination of several different cell surface markers are used to separate the rare HSCs from the surrounding blood cells. HSCs lack expression of mature blood cell markers and are thus, called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate HSCs. In addition, HSCs are characterised by their small size and low staining with vital dyes such as rhodamine 123 or Hoechst 33342.

References

  1. 1 2 Medvinsky, A. L.; Samoylina, N. L.; Müller, A. M.; Dzierzak, E. A. (1993-07-01). "An early pre-liver intraembryonic source of CFU-S in the developing mouse". Nature. 364 (6432): 64–67. Bibcode:1993Natur.364...64M. doi:10.1038/364064a0. ISSN   0028-0836. PMID   8316298. S2CID   4345606.
  2. 1 2 3 Müller, A. M.; Medvinsky, A.; Strouboulis, J.; Grosveld, F.; Dzierzak, E. (July 1994). "Development of hematopoietic stem cell activity in the mouse embryo". Immunity. 1 (4): 291–301. doi:10.1016/1074-7613(94)90081-7. ISSN   1074-7613. PMID   7889417.
  3. 1 2 3 4 Medvinsky, Alexander; Dzierzak, Elaine (September 1996). "Definitive Hematopoiesis Is Autonomously Initiated by the AGM Region". Cell. 86 (6): 897–906. doi:10.1016/s0092-8674(00)80165-8. hdl:1765/57137. ISSN   0092-8674. PMID   8808625. S2CID   3330712.
  4. 1 2 Kauts, Mari-Liis; Vink, Chris S.; Dzierzak, Elaine (November 2016). "Hematopoietic (stem) cell development - how divergent are the roads taken?". FEBS Letters. 590 (22): 3975–3986. doi:10.1002/1873-3468.12372. ISSN   1873-3468. PMC   5125883 . PMID   27543859.
  5. 1 2 3 4 Dzierzak, Elaine; Bigas, Anna (2018-05-03). "Blood Development: Hematopoietic Stem Cell Dependence and Independence". Cell Stem Cell. 22 (5): 639–651. doi:10.1016/j.stem.2018.04.015. hdl: 10230/36965 . ISSN   1875-9777. PMID   29727679.
  6. ↑ Cumano, Ana; Godin, Isabelle (2007). "Ontogeny of the hematopoietic system". Annual Review of Immunology. 25: 745–785. doi:10.1146/annurev.immunol.25.022106.141538. ISSN   0732-0582. PMID   17201678.
  7. ↑ Ivanovs, Andrejs; Rybtsov, Stanislav; Welch, Lindsey; Anderson, Richard A.; Turner, Marc L.; Medvinsky, Alexander (2011-11-21). "Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region". The Journal of Experimental Medicine. 208 (12): 2417–2427. doi:10.1084/jem.20111688. ISSN   1540-9538. PMC   3256972 . PMID   22042975.
  8. 1 2 de Bruijn, Marella F. T. R.; Ma, Xiaoqian; Robin, Catherine; Ottersbach, Katrin; Sanchez, Maria-Jose; Dzierzak, Elaine (May 2002). "Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta". Immunity. 16 (5): 673–683. doi: 10.1016/s1074-7613(02)00313-8 . ISSN   1074-7613. PMID   12049719.
  9. ↑ Taoudi, Samir; Medvinsky, Alexander (2007-05-29). "Functional identification of the hematopoietic stem cell niche in the ventral domain of the embryonic dorsal aorta". Proceedings of the National Academy of Sciences of the United States of America. 104 (22): 9399–9403. Bibcode:2007PNAS..104.9399T. doi: 10.1073/pnas.0700984104 . ISSN   0027-8424. PMC   1890506 . PMID   17517650.
  10. ↑ Boisset, Jean-Charles; van Cappellen, Wiggert; Andrieu-Soler, Charlotte; Galjart, Niels; Dzierzak, Elaine; Robin, Catherine (2010-03-04). "In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium". Nature. 464 (7285): 116–120. Bibcode:2010Natur.464..116B. doi:10.1038/nature08764. ISSN   1476-4687. PMID   20154729. S2CID   4369315.
  11. ↑ Bertrand, Julien Y.; Chi, Neil C.; Santoso, Buyung; Teng, Shutian; Stainier, Didier Y. R.; Traver, David (2010-03-04). "Haematopoietic stem cells derive directly from aortic endothelium during development". Nature. 464 (7285): 108–111. Bibcode:2010Natur.464..108B. doi:10.1038/nature08738. ISSN   1476-4687. PMC   2858358 . PMID   20154733.
  12. ↑ Kissa, Karima; Herbomel, Philippe (2010-03-04). "Blood stem cells emerge from aortic endothelium by a novel type of cell transition". Nature. 464 (7285): 112–115. Bibcode:2010Natur.464..112K. doi:10.1038/nature08761. ISSN   1476-4687. PMID   20154732. S2CID   243694.
  13. 1 2 Eich, Christina; Arlt, Jochen; Vink, Chris S.; Solaimani Kartalaei, Parham; Kaimakis, Polynikis; Mariani, Samanta A.; van der Linden, Reinier; van Cappellen, Wiggert A.; Dzierzak, Elaine (2018-01-02). "In vivo single cell analysis reveals Gata2 dynamics in cells transitioning to hematopoietic fate". The Journal of Experimental Medicine. 215 (1): 233–248. doi:10.1084/jem.20170807. ISSN   1540-9538. PMC   5748852 . PMID   29217535.
  14. ↑ Ottersbach, Katrin (2019-04-30). "Endothelial-to-haematopoietic transition: an update on the process of making blood". Biochemical Society Transactions. 47 (2): 591–601. doi:10.1042/BST20180320. ISSN   1470-8752. PMC   6490701 . PMID   30902922.
  15. 1 2 Solaimani Kartalaei, Parham; Yamada-Inagawa, Tomoko; Vink, Chris S.; de Pater, Emma; van der Linden, Reinier; Marks-Bluth, Jonathon; van der Sloot, Anthon; van den Hout, Mirjam; Yokomizo, Tomomasa; van Schaick-Solernó, M. Lucila; Delwel, Ruud (2015-01-12). "Whole-transcriptome analysis of endothelial to hematopoietic stem cell transition reveals a requirement for Gpr56 in HSC generation". The Journal of Experimental Medicine. 212 (1): 93–106. doi:10.1084/jem.20140767. ISSN   1540-9538. PMC   4291529 . PMID   25547674.
  16. 1 2 3 4 Vink, Chris Sebastiaan; Calero-Nieto, Fernando Jose; Wang, Xiaonan; Maglitto, Antonio; Mariani, Samanta Antonella; Jawaid, Wajid; Göttgens, Berthold; Dzierzak, Elaine (2020-05-12). "Iterative Single-Cell Analyses Define the Transcriptome of the First Functional Hematopoietic Stem Cells". Cell Reports. 31 (6): 107627. doi:10.1016/j.celrep.2020.107627. ISSN   2211-1247. PMC   7225750 . PMID   32402290.
  17. 1 2 Sánchez, M. J.; Holmes, A.; Miles, C.; Dzierzak, E. (December 1996). "Characterization of the first definitive hematopoietic stem cells in the AGM and liver of the mouse embryo". Immunity. 5 (6): 513–525. doi: 10.1016/s1074-7613(00)80267-8 . ISSN   1074-7613. PMID   8986712.
  18. ↑ Robin, Catherine; Ottersbach, Katrin; Boisset, Jean-Charles; Oziemlak, Aneta; Dzierzak, Elaine (2011-05-12). "CD41 is developmentally regulated and differentially expressed on mouse hematopoietic stem cells". Blood. 117 (19): 5088–5091. doi:10.1182/blood-2011-01-329516. ISSN   1528-0020. PMC   3109535 . PMID   21415271.
  19. ↑ Kaimakis, Polynikis; de Pater, Emma; Eich, Christina; Solaimani Kartalaei, Parham; Kauts, Mari-Liis; Vink, Chris S.; van der Linden, Reinier; Jaegle, Martine; Yokomizo, Tomomasa; Meijer, Dies; Dzierzak, Elaine (2016-03-17). "Functional and molecular characterization of mouse Gata2-independent hematopoietic progenitors". Blood. 127 (11): 1426–1437. doi:10.1182/blood-2015-10-673749. ISSN   1528-0020. PMC   4797020 . PMID   26834239.
  20. ↑ North, Trista E.; de Bruijn, Marella F. T. R.; Stacy, Terryl; Talebian, Laleh; Lind, Evan; Robin, Catherine; Binder, Michael; Dzierzak, Elaine; Speck, Nancy A. (May 2002). "Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo". Immunity. 16 (5): 661–672. doi: 10.1016/s1074-7613(02)00296-0 . ISSN   1074-7613. PMID   12049718.
  21. ↑ Chen, Michael J.; Yokomizo, Tomomasa; Zeigler, Brandon M.; Dzierzak, Elaine; Speck, Nancy A. (2009-02-12). "Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter". Nature. 457 (7231): 887–891. Bibcode:2009Natur.457..887C. doi:10.1038/nature07619. ISSN   1476-4687. PMC   2744041 . PMID   19129762.
  22. ↑ Kumano, Keiki; Chiba, Shigeru; Kunisato, Atsushi; Sata, Masataka; Saito, Toshiki; Nakagami-Yamaguchi, Etsuko; Yamaguchi, Tomoyuki; Masuda, Shigeo; Shimizu, Kiyoshi; Takahashi, Tokiharu; Ogawa, Seishi (May 2003). "Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells". Immunity. 18 (5): 699–711. doi: 10.1016/s1074-7613(03)00117-1 . ISSN   1074-7613. PMID   12753746.
  23. ↑ Crisan, Mihaela; Kartalaei, Parham Solaimani; Vink, Chris S.; Yamada-Inagawa, Tomoko; Bollerot, Karine; van IJcken, Wilfred; van der Linden, Reinier; de Sousa Lopes, Susana M. Chuva; Monteiro, Rui; Mummery, Christine; Dzierzak, Elaine (2015-10-29). "Corrigendum: BMP signalling differentially regulates distinct haematopoietic stem cell types". Nature Communications. 6: 8793. Bibcode:2015NatCo...6.8793C. doi:10.1038/ncomms9793. ISSN   2041-1723. PMC   7188459 . PMID   26510935.
  24. ↑ Peeters M, Ottersbach K, Bollerot K, Orelio C, de Bruijn M, Wijgerde M, Dzierzak E (August 2009). "Ventral embryonic tissues and Hedgehog proteins induce early AGM hematopoietic stem cell development". Development. 136 (15): 2613–21. doi:10.1242/dev.034728. PMC   2709067 . PMID   19570846.
  25. 1 2 Dzierzak, Elaine; Speck, Nancy A. (February 2008). "Of lineage and legacy: the development of mammalian hematopoietic stem cells". Nature Immunology. 9 (2): 129–136. doi:10.1038/ni1560. ISSN   1529-2916. PMC   2696344 . PMID   18204427.
  26. ↑ Orkin, Stuart H.; Zon, Leonard I. (2008-02-22). "Hematopoiesis: an evolving paradigm for stem cell biology". Cell. 132 (4): 631–644. doi:10.1016/j.cell.2008.01.025. ISSN   1097-4172. PMC   2628169 . PMID   18295580.
  27. ↑ Kumaravelu P, Hook L, Morrison AM, Ure J, Zhao S, Zuyev S, Ansell J, Medvinsky A (November 2002). "Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver". Development. 129 (21): 4891–9. doi:10.1242/dev.129.21.4891. PMID   12397098.
  28. 1 2 Medvinsky AL, Dzierzak EA (1998). "Development of the definitive hematopoietic hierarchy in the mouse". Dev. Comp. Immunol. 22 (3): 289–301. doi:10.1016/S0145-305X(98)00007-X. PMID   9700459.
  29. ↑ Ciau-Uitz A, Walmsley M, Patient R (September 2000). "Distinct origins of adult and embryonic blood in Xenopus". Cell. 102 (6): 787–96. doi: 10.1016/S0092-8674(00)00067-2 . PMID   11030622. S2CID   1605911.
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