Abstract
Hematopoietic stem cells first arise in the mammalian embryo in a primitive state, not capable of reconstituting hematopoiesis in irradiated adult recipients. As development proceeds, these cells eventually mature to acquire definitive, adult characteristics, including adult reconstitution ability. Mouse embryonic stem cells induced to undergo hematopoiesis in vitro readily generate primitive hematopoietic stem cells but rarely generate the definitive type. Recent work has stimulated a new appreciation of the events involved in the developmental maturation of hematopoietic stem cells. Application of this knowledge to in vitro differentiation systems will be critical to the successful development of hematopoietic therapies from embryonic stem cells.
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References
Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–1147.
Hwang WS, Ryu YJ, Park JH, et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science. 2004;303:1669–1674.
Beatty PG, Boucher KM, Mori M, Milford EL. Probability of finding HLA-mismatched related or unrelated marrow or cord blood donors. Hum Immunol. 2000;61:834–840.
Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003;102:1915–1919.
Wagner JE, Rosenthal J, Sweetman R, et al. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood. 1996;88:795–802.
Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. 1953;172:603–606.
Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature. 1984;307:168–170.
Fairchild PJ, Cartland S, Nolan KF, Waldmann H. Embryonic stem cells and the challenge of transplantation tolerance. Trends Immunol. 2004;25:465–470.
Shizuru JA, Weissman IL, Kernoff R, Masek M, Scheffold YC. Purified hematopoietic stem cell grafts induce tolerance to alloantigens and can mediate positive and negative T cell selection. Proc Natl Acad Sci USA. 2000;97:9555–9560.
Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol. 1985;87:27–45.
Coucouvanis E, Martin GR. Signals for death and survival: a two- step mechanism for cavitation in the vertebrate embryo. Cell. 1995; 83:279–287.
Coucouvanis E, Martin GR. BMP signaling plays a role in visceral endoderm differentiation and cavitation in the early mouse embryo. Development. 1999;126:535–546.
Hole N, Graham GJ, Menzel U, Ansell JD. A limited temporal window for the derivation of multilineage repopulating hematopoietic progenitors during embryonal stem cell differentiation in vitro. Blood. 1996;88:1266–1276.
Potocnik AJ, Kohler H, Eichmann K. Hemato-lymphoid in vivo reconstitution potential of subpopulations derived from in vitro differentiated embryonic stem cells. Proc Natl Acad Sci USA. 1997;94:10295–10300.
Muller AM, Dzierzak EA. ES cells have only a limited lymphopoietic potential after adoptive transfer into mouse recipients. Development. 1993;118:1343–1351.
Haar JL, Ackerman GA. A phase and electron microscopic study of vasculogenesis and erythropoiesis in the yolk sac of the mouse. Anat Rec. 1971;170:199–223.
Kumaravelu P, Hook L, Morrison AM, et al. 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. 2002;129:4891–4899.
Cumano A, Dieterlen-Lièvre F, Godin I. Lymphoid potential, probed before circulation in mouse, is restricted to caudal intraembryonic splanchnopleura. Cell. 1996;86:907–916.
Garcia-Porrero JA, Godin IE, Dieterlen-Lièvre F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat Embryol. 1995;192:425–435.
Palis J, Robertson S, Kennedy M, Wall C, Keller G. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development. 1999;126:5073–5084.
Cumano A, Ferraz JC, Klaine M, Santo JP, Godin I. Intraembryonic, but not yolk sac hematopoietic precursors, isolated before circulation, provide long-term multilineage reconstitution. Immunity. 2001;15:477–485.
Yoder MC, Hiatt K, Mukherjee P. In vivo repopulating hematopoietic stem cells are present in the murine yolk sac at day 9.0 post- coitus. Proc Natl Acad Sci USA. 1997;94:6776–6780.
Yoder MC, Hiatt K, Dutt P, Mukherjee P, Bodine DM, Orlic D. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity. 1997;7:335–344.
Weissman I, Papaioannou V, Gardner R. Fetal hematopoietic origins of the adult hematolymphoid system. In: Clarkson B, Marks PA, Till JE, eds. Differentiation of Normal and Neoplastic Hematopoietic Cells. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 1978: 33–47.
Christensen JL, Wright DE, Wagers AJ, Weissman IL. Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol. 2004;2:E75.
Morrison SJ, Hemmati HD, Wandycz AM, Weissman IL. The purification and characterization of fetal liver hematopoietic stem cells. Proc Natl Acad Sci USA. 1995;92:10302–10306.
Naik UP, Parise LV. Structure and function of platelet alpha IIb beta 3. Curr Opin Hematol. 1997;4:317–322.
Berridge MV, Ralph SJ, Tan AS. Cell-lineage antigens of the stem cell-megakaryocyte-platelet lineage are associated with the platelet IIb-IIIa glycoprotein complex. Blood. 1985;66:76–85.
Tropel P, Roullot V, Vernet M, et al. A 2.7-kb portion of the 5′ flanking region of the murine glycoprotein alphaIIb gene is transcriptionally active in primitive hematopoietic progenitor cells. Blood. 1997;90:2995–3004.
Ody C, Vaigot P, Quere P, Imhof BA, Corbel C. Glycoprotein IIb- IIIa is expressed on avian multilineage hematopoietic progenitor cells. Blood. 1999;93:2898–2906.
Corbel C, Salaun J. AlphaIIb integrin expression during development of the murine hemopoietic system. Dev Biol. 2002;243:301–311.
Mitjavila-Garcia MT, Cailleret M, Godin I, et al. Expression of CD41 on hematopoietic progenitors derived from embryonic hematopoietic cells. Development. 2002;129:2003–2013.
Mikkola HK, Fujiwara Y, Schlaeger TM, Traver D, Orkin SH. Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. Blood. 2003;101:508–516.
Ferkowicz MJ, Starr M, Xie X, et al. CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo. Blood. 2003;101:508–516.
Emambokus NR, Frampton J. The glycoprotein IIb molecule is expressed on early murine hematopoietic progenitors and regulates their numbers in sites of hematopoiesis. Immunity. 2003;19:33–45.
Kyba M, Daley GQ. Hematopoiesis from embryonic stem cells: lessons from and for ontogeny. Exp Hematol. 2003;31:994–1006.
Sequeira Lopez ML, Chernavvsky DR, Nomasa T, Wall L, Yanagisawa M, Gomez RA. The embryo makes red blood cell progenitors in every tissue simultaneously with blood vessel morphogenesis. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1126-R1137.
Caprioli A, Jaffredo T, Gautier R, Dubourg C, Dieterlen-Lièvre F. Blood-borne seeding by hematopoietic and endothelial precursors from the allantois. Proc Natl Acad Sci USA. 1998;95:1641–1646.
Alvarez-Silva M, Belo-Diabangouaya P, Salaun J, Dieterlen-Lièvre F. Mouse placenta is a major hematopoietic organ. Development 2003;130:5437–5444.
Mikkola HK, Gekas C, Dieterlen-Lièvre F, Orkin SH. Placenta is a niche for hematopoietic stem cells. Blood. 2004;104:730a.
Kyba M, Perlingeiro RC, Daley GQ. HoxB4 confers definitive lymphoid- myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell. 2002;109:29–37.
Pilat S, Carotta S, Schiedlmeier B, et al. HOXB4 enforces equivalent fates of ES-cell-derived and adult hematopoietic cells. Blood. 2004;104:144a.
Kyba M, Perlingeiro RC, Hoover RR, Lu CW, Pierce J, Daley GQ. Enhanced hematopoietic differentiation of embryonic stem cells conditionally expressing Stat5. Proc Natl Acad Sci USA. 2003;100(suppl 1):11904–11910.
Iacovino M, Osawa M, Kyba M. HoxAlO dramatically alters the immunophenotype of early hematopoietic progenitors derived in vitro from ES cells. Blood. 2004;104:881a.
Davidson AJ, Ernst P, Wang Y, et al. Cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes. Nature. 2003;425:300–306.
Wang Y, Yates F, Dikovskaia E, et al. Derivation of hematopoietic stem cells from embryonic stem cells. Blood. 2004;104:68a.
Davidson AJ, Wang Y, Daley GQ, Zon LI. Inhibition of retinoic acid signaling by the cdx-hox pathway is essential for blood cell formation during embryogenesis. Blood. 2004;104:42a.
Kim JY, Sawada A, Tokimasa S, et al. Defective long-term repopulating ability in hematopoietic stem cells lacking the Polycomb- group gene rae28. Eur J Haematol. 2004;73:75–84.
Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003;423:302–305.
Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature. 2003;423:255–260.
Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci USA. 2001;98:10716–10721.
Kaufman DS, Woll PS, Martin CH, Linehan JL, Tian X. CD34+ cells derived from human embryonic stem cells demonstrate hematopoietic stem cell potential in vitro and in vivo. Blood. 2004;104:163a.
Narayan AD, Chase JL, Ersek A, et al. Human embryonic stem cell (hESC)-derived hematopoietic elements are capable of engrafting primary as well as secondary fetal sheep recipients. Blood. 2004;104:733a.
Thomson JA, Kalishman J, Golos TG, et al. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA. 1995;92:7844–7848.
Thomson JA, Kalishman J, Golos TG, Durning M, Hearn JP. Pluripotent cell lines derived from common marmoset (Callithrix jacchus) blastocysts. Biol Reprod. 1996;55:254–259..
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Kyba, M. Genesis of Hematopoietic Stem Cells In Vitro and In Vivo: New Insights into Developmental Maturation. Int J Hematol 81, 275–280 (2005). https://doi.org/10.1532/IJH97.04192
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DOI: https://doi.org/10.1532/IJH97.04192