Abstract
Understanding how blood cells are generated is important from a biological perspective but also has potential implications in the treatment of blood diseases. Such knowledge could potentially lead to defining new conditions to amplify hematopoietic stem cells (HSCs) or could translate into new methods to produce HSCs, or other types of blood cells, from human embryonic stem cells or induced pluripotent stem cells. Additionally, as most key transcription factors regulating early hematopoietic development have also been implicated in various types of leukemia, understanding their function during normal development could result in a better comprehension of their roles during abnormal hematopoiesis in leukemia. In this review, we discuss our current understanding of the molecular and cellular mechanisms of blood development from the earliest hematopoietic precursor, the hemangioblast, a precursor for both endothelial and hematopoietic cell lineages.
Similar content being viewed by others
References
Sabin FR (1920) Studies on the origin of blood vessels and of red corpuscules as seen in the living blastoderm of the chick during the second day of incubation: contributions to embryology. Contrib Embryol 9:213–262
Murray PDF (1932) The development in vitro of the blood of the early chick embryo. Proc R Soc Lond 11:497–521
Palis J, Robertson S, Kennedy M, Wall C, Keller G (1999) Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126:5073–5084
Klimchenko O, Mori M, Distefano A, Langlois T, Larbret F, Lecluse Y, Feraud O, Vainchenker W, Norol F, Debili N (2009) A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell-derived primitive hematopoiesis. Blood 114:1506–1517
Tober J, Koniski A, McGrath KE, Vemishetti R, Emerson R, de Mesy-Bentley KK, Waugh R, Palis J (2007) The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood 109:1433–1441
Kennedy M, Firpo M, Choi K, Wall C, Robertson S, Kabrun N, Keller G (1997) A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature 386:488–493
Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G (1998) A common precursor for hematopoietic and endothelial cells. Development 125:725–732
Fehling HJ, Lacaud G, Kubo A, Kennedy M, Robertson S, Keller G, Kouskoff V (2003) Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation. Development 130:4217–4227
Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G (2009) The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457:892–895
Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G (2004) Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432:625–630
Vogeli KM, Jin SW, Martin GR, Stainier DY (2006) A common progenitor for haematopoietic and endothelial lineages in the zebrafish gastrula. Nature 443:337–339
Ueno H, Weissman IL (2006) Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev Cell 11:519–533
Lugus JJ, Park C, Ma YD, Choi K (2009) Both primitive and definitive blood cells are derived from Flk-1+ mesoderm. Blood 113:563–566
Gunsilius E, Duba HC, Petzer AL, Kahler CM, Grunewald K, Stockhammer G, Gabl C, Dirnhofer S, Clausen J, Gastl G (2000) Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet 355:1688–1691
Pelosi E, Valtieri M, Coppola S, Botta R, Gabbianelli M, Lulli V, Marziali G, Masella B, Muller R, Sgadari C, Testa U, Bonanno G, Peschle C (2002) Identification of the hemangioblast in postnatal life. Blood 100:3203–3208
Bailey AS, Jiang S, Afentoulis M, Baumann CI, Schroeder DA, Olson SB, Wong MH, Fleming WH (2004) Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood 103:13–19
Grant MB, May WS, Caballero S, Brown GA, Guthrie SM, Mames RN, Byrne BJ, Vaught T, Spoerri PE, Peck AB, Scott EW (2002) Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat Med 8:607–612
Jiang S, Bailey AS, Goldman DC, Swain JR, Wong MH, Streeter PR, Fleming WH (2008) Hematopoietic stem cells contribute to lymphatic endothelium. PLoS ONE 3:e3812
Medvinsky AL, Samoylina NL, Muller AM, Dzierzak EA (1993) An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 364:64–67
de Bruijn MF, Speck NA, Peeters MC, Dzierzak E (2000) Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. Embo J 19:2465–2474
Rhodes KE, Gekas C, Wang Y, Lux CT, Francis CS, Chan DN, Conway S, Orkin SH, Yoder MC, Mikkola HK (2008) The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell 2:252–263
Zeigler BM, Sugiyama D, Chen M, Guo Y, Downs KM, Speck NA (2006) The allantois and chorion, when isolated before circulation or chorio-allantoic fusion, have hematopoietic potential. Development 133:4183–4192
Dieterlen-Lievre F, Martin C (1981) Diffuse intraembryonic hemopoiesis in normal and chimeric avian development. Dev Biol 88:180–191
Garcia-Porrero JA, Godin IE, Dieterlen-Lievre F (1995) Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat Embryol (Berl) 192:425–435
Tavian M, Coulombel L, Luton D, Clemente HS, Dieterlen-Lievre F, Peault B (1996) Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87:67–72
Jaffredo T, Gautier R, Brajeul V, Dieterlen-Lievre F (2000) Tracing the progeny of the aortic hemangioblast in the avian embryo. Dev Biol 224:204–214
Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lievre F (1998) Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125:4575–4583
Nishikawa SI, Nishikawa S, Kawamoto H, Yoshida H, Kizumoto M, Kataoka H, Katsura Y (1998) In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. Immunity 8:761–769
Eilken HM, Nishikawa S, Schroeder T (2009) Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457:896–900
Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA (2009) Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457:887–891
Zovein AC, Hofmann JJ, Lynch M, French WJ, Turlo KA, Yang Y, Becker MS, Zanetta L, Dejana E, Gasson JC, Tallquist MD, Iruela-Arispe ML (2008) Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell 3:625–636
Lecuyer E, Hoang T (2004) SCL: from the origin of hematopoiesis to stem cells and leukemia. Exp Hematol 32:11–24
Shivdasani RA, Mayer EL, Orkin SH (1995) Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373:432–434
Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH (1996) The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 86:47–57
Endoh M, Ogawa M, Orkin S, Nishikawa S (2002) SCL/tal-1-dependent process determines a competence to select the definitive hematopoietic lineage prior to endothelial differentiation. EMBO J 21:6700–6708
D’Souza SL, Elefanty AG, Keller G (2005) SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblast but not for its development. Blood 105:3862–3870
Schlaeger TM, Mikkola HK, Gekas C, Helgadottir HB, Orkin SH (2005) Tie2Cre-mediated gene ablation defines the stem-cell leukemia gene (SCL/tal1)-dependent window during hematopoietic stem-cell development. Blood 105:3871–3874
Gering M, Rodaway AR, Gottgens B, Patient RK, Green AR (1998) The SCL gene specifies haemangioblast development from early mesoderm. EMBO J 17:4029–4045
Ismailoglu I, Yeamans G, Daley GQ, Perlingeiro RC, Kyba M (2008) Mesodermal patterning activity of SCL. Exp Hematol 36:1593–1603
Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M (1991) t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc Natl Acad Sci USA 88:10431–10434
Look AT (1997) Oncogenic transcription factors in the human acute leukemias. Science 278:1059–1064
Schindler JW, Van Buren D, Foudi A, Krejci O, Qin J, Orkin SH, Hock H (2009) TEL-AML1 corrupts hematopoietic stem cells to persist in the bone marrow and initiate leukemia. Cell Stem Cell 5:43–53
Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR (1996) AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84:321–330
Yokomizo T, Hasegawa K, Ishitobi H, Osato M, Ema M, Ito Y, Yamamoto M, Takahashi S (2008) Runx1 is involved in primitive erythropoiesis in the mouse. Blood 111:4075–4080
Lacaud G, Gore L, Kennedy M, Kouskoff V, Kingsley P, Hogan C, Carlsson L, Speck N, Palis J, Keller G (2002) Runx1 is essential for hematopoietic commitment at the hemangioblast stage of development in vitro. Blood 100:458–466
Li Z, Chen MJ, Stacy T, Speck NA (2006) Runx1 function in hematopoiesis is required in cells that express Tek. Blood 107:106–110
Liakhovitskaia A, Gribi R, Stamateris E, Villain G, Jaffredo T, Wilkie R, Gilchrist D, Yang J, Ure J, Medvinsky A (2009) Restoration of Runx1 expression in the Tie2 cell compartment rescues definitive hematopoietic stem cells and extends life of Runx1 knockout animals until birth. Stem Cells 27:1616–1624
Hoogenkamp M, Lichtinger M, Krysinska H, Lancrin C, Clarke D, Williamson A, Mazzarella L, Ingram R, Jorgensen H, Fisher A, Tenen DG, Kouskoff V, Lacaud G, Bonifer C (2009) Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program. Blood 114:299–309
Cheng X, Huber TL, Chen VC, Gadue P, Keller GM (2008) Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast. Development 135:3447–3458
Burns CE, Traver D, Mayhall E, Shepard JL, Zon LI (2005) Hematopoietic stem cell fate is established by the Notch–Runx pathway. Genes Dev 19:2331–2342
Nakagawa M, Ichikawa M, Kumano K, Goyama S, Kawazu M, Asai T, Ogawa S, Kurokawa M, Chiba S (2006) AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis. Blood 108:3329–3334
Yokomizo T, Takahashi S, Mochizuki N, Kuroha T, Ema M, Wakamatsu A, Shimizu R, Ohneda O, Osato M, Okada H, Komori T, Ogawa M, Nishikawa S, Ito Y, Yamamoto M (2007) Characterization of GATA-1(+) hemangioblastic cells in the mouse embryo. Embo J 26:184–196
Lugus JJ, Chung YS, Mills JC, Kim SI, Grass J, Kyba M, Doherty JM, Bresnick EH, Choi K (2007) GATA2 functions at multiple steps in hemangioblast development and differentiation. Development 134:393–405
Liu F, Walmsley M, Rodaway A, Patient R (2008) Fli1 acts at the top of the transcriptional network driving blood and endothelial development. Curr Biol 18:1234–1240
Guo Y, Chan R, Ramsey H, Li W, Xie X, Shelley WC, Martinez-Barbera JP, Bort B, Zaret K, Yoder M, Hromas R (2003) The homeoprotein Hex is required for hemangioblast differentiation. Blood 102:2428–2435
Kubo A, Chen V, Kennedy M, Zahradka E, Daley GQ, Keller G (2005) The homeobox gene HEX regulates proliferation and differentiation of hemangioblasts and endothelial cells during ES cell differentiation. Blood 105:4590–4597
Lee D, Park C, Lee H, Lugus JJ, Kim SH, Arentson E, Chung YS, Gomez G, Kyba M, Lin S, Janknecht R, Lim DS, Choi K (2008) ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell 2:497–507
Patterson LJ, Gering M, Eckfeldt CE, Green AR, Verfaillie CM, Ekker SC, Patient R (2007) The transcription factors Scl and Lmo2 act together during development of the hemangioblast in zebrafish. Blood 109:2389–2398
Perlingeiro RC (2007) Endoglin is required for hemangioblast and early hematopoietic development. Development 134:3041–3048
Pimanda JE, Donaldson IJ, de Bruijn MF, Kinston S, Knezevic K, Huckle L, Piltz S, Landry JR, Green AR, Tannahill D, Gottgens B (2007) The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity. Proc Natl Acad Sci USA 104:840–845
Pimanda JE, Chan WY, Wilson NK, Smith AM, Kinston S, Knezevic K, Janes ME, Landry JR, Kolb-Kokocinski A, Frampton J, Tannahill D, Ottersbach K, Follows GA, Lacaud G, Kouskoff V, Gottgens B (2008) Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code. Blood 112:4512–4522
Pearson S, Sroczynska P, Lacaud G, Kouskoff V (2008) The stepwise specification of embryonic stem cells to hematopoietic fate is driven by sequential exposure to Bmp4, activin A, bFGF and VEGF. Development 135:1525–1535
Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T, Naito M, Nakao K (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408:92–96
Acknowledgements
We thank Sarah Lewis (Paterson Institute for Cancer Research) for critical reading of the manuscript. C.L., P.S., A.G.S, A.G., C.F., V.K., and G.L. are funded by Cancer Research UK.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lancrin, C., Sroczynska, P., Serrano, A.G. et al. Blood cell generation from the hemangioblast. J Mol Med 88, 167–172 (2010). https://doi.org/10.1007/s00109-009-0554-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-009-0554-0