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Ontogeny of Erythropoiesis James Palis

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Ontogeny of Erythropoiesis James Palis Ontogeny of erythropoiesis James Palis University of Rochester Medical Center, Rochester, Purpose of review New York, USA The present study review examines the current understanding of the ontogeny of Correspondence to James Palis, MD, University of erythropoiesis with a focus on the emergence of the embryonic (primitive) erythroid Rochester Medical Center, Department of Pediatrics and Center for Pediatric Biomedical Research, Box lineage and on the similarities and differences between the primitive and the fetal/adult 703, 601 Elmwood Ave., Rochester, NY 14642, USA (definitive) forms of erythroid cell maturation. Tel: +1 585 275 5098; fax: +1 585 276 0232; e-mail: [email protected] Recent findings Primitive erythroid precursors in the mouse embryo and cultured in vitro from human embryonic stem cells undergo ‘maturational’ globin switching as they differentiate Current Opinion in Hematology 2008, 15:155– 161 terminally. The appearance of a transient population of primitive ‘pyrenocytes’ (extruded nuclei) in the fetal bloodstream indicates that primitive erythroblasts enucleate by nuclear extrusion. In-vitro differentiation of human embryonic stem cells recapitulates hematopoietic ontogeny reminiscent of the murine yolk sac, including overlapping waves of hemangioblast, primitive, erythroid, and definitive erythroid progenitors. Definitive erythroid potential in zebrafish embryos, like that in mice, initially arises prior to, and independent of, hematopoietic stem cell emergence in the region of the aorta. Maturation of definitive erythroid cells within macrophage islands promotes erythroblast–erythroblast and erythroblast–stromal interactions that regulate red cell output. Summary The study of embryonic development in several different model systems, as well as in cultured human embryonic stem cells, continues to provide important insights into the ontogeny of erythropoiesis. Contrasting the similarities and differences between primitive and definitive erythropoiesis will lead to an improved understanding of erythroblast maturation and the terminal steps of erythroid differentiation. Keywords definitive erythropoiesis, hemangioblast, primitive erythropoiesis, pyrenocyte Curr Opin Hematol 15:155–161 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1065-6251 ination of embryonic and fetal blood cell morphology, Introduction however, revealed that primitive red cells undergo a The red cells of mammals are unique in the animal synchronous wave of maturation in the bloodstream. Four kingdom as they circulate as enucleated cells. In contrast, years ago, it was discovered that late-stage primitive the fully mature red cells of birds, amphibians, and fish erythroblasts in the mouse embryo complete their matu- remain nucleated [1]. A century ago, examination of ration by enucleating and continuing to circulate for mammalian embryos revealed the presence of distinct several more days as erythrocytes [3]. The specification nucleated and enucleated red cells [2]. The continuous of hematopoiesis in mammalian embryos was discussed circulation of small, enucleated erythrocytes during fetal last in Current Opinion in Hematology 3 years ago [4]. Here, and postnatal life (‘definitive’ erythropoiesis) was distin- recent insights regarding the ontogeny of erythropoiesis guished from ‘primitive’ erythropoiesis, characterized by and the maturation of the primitive and definitive ery- the transient circulation of large, nucleated red cells that throid lineages will be reviewed. originate in the yolk sac. Similarly, it was recognized that primitive erythropoiesis originates in the yolk sac and intermediate cell mass of chicken and zebrafish embryos, Emergence of primitive erythropoiesis in the respectively. As mammalian primitive erythroblasts cir- early embryo culate as nucleated cells and are confined to the embryo, The initial generation of erythroid cells in the embryo they have been thought of as a ‘primitive’ form of of mammalian and nonmammalian organisms depends erythropoiesis that shares many characteristics with the on the formation of mesoderm cells that migrate through nucleated red cells of nonmammalian vertebrates. Exam- the primitive streak and contribute to the formation of 1065-6251 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 156 Erythroid system and its diseases intraembryonic as well as extraembryonic structures such with, or soon after, the onset of cardiac contractions as the yolk sac and the placenta in mammals. Immature [16,17]. Over the next 8 days, primitive erythroid cells primitive erythroid cells rapidly pool into so-called blood mature in a synchronous cohort as they undergo changes islands soon after the start of gastrulation in the yolk sac of well recognized in maturing definitive erythroid precur- mammalian and avian embryos [5,6]. These blood islands sors, including a limited number of cell divisions, accu- become enveloped by endothelial cells, which form the mulation of increasing amounts of hemoglobin, nuclear initial vascular plexus of the yolk sac (reviewed by condensation, a progressive decrease in cell size, and Ferkowicz and Yoder, [7]). ultimately enucleation [3,18]. Many of these findings have recently been confirmed using a transgenic mouse The appearance of primitive erythroid cells and endo- expressing the enhanced green fluorescent protein thelial cells at the same time and place within the early (eGFP) in primitive erythroid cells [19]. Interestingly, conceptus has long suggested that these lineages share a circulating primitive erythroblasts express several adhe- common developmental origin. A unique blast colony- sion molecules that could mediate interactions with other forming cell (Blast-CFC) containing both hematopoietic cell types [19]. and endothelial cell potential has been identified in both cultured embryonic stem cells and mouse embryos [8,9]. Coincident with primitive erythroblast enucleation, the Consistent with the hypothesis that the first blood appearance of a transient population of very small, cells arise from a hemangioblast precursor, clonal studies nucleated cells with a rim of ey-globin-positive cyto- reveal that a small number of GATA1-expressing cells in plasm was noted in the circulation of mouse embryos blood islands of mouse yolk sacs have endothelial as well [20]. These cells are reminiscent of extruded nuclei as primitive erythroid cell potential [10]. Furthermore, [21], which are the product of enucleation of late-stage the transcription factors GATA2 and endoglin, both of erythroblasts (Fig. 1). The extruded nuclei from defini- which function in hematopoietic stem cells (HSC), have tive erythroid cells undergo rapid loss of the phosphati- each been shown to regulate hemangioblast precursors dylserine asymmetry of the cell membrane and are [11,12]. The close association of the primitive erythroid engulfed by macrophage cells [22]. As the cell membrane and endothelial lineages is further supported by the plays an important role in the biology of these cells, finding that the primitive erythroid lineage in the mouse extruded nucleus is an inadequate term and ‘pyreno- emerges from mesodermal cells that express markers cytes’, derived from the Greek word ‘pyren’ (the pit of a found in adult endothelial cells, including flk-1, vascular stone fruit), has been proposed as a more appropriate endothelial cadherin, tie-2, and PECAM-1 [13]. There is name for this very transient cell [20]. The discovery of an increasing evidence, however, that suggests that primitive pyrenocytes in the fetal bloodstream suggests many, if not most, yolk sac vascular cells in the conceptus that late-stage primitive erythroblasts enucleate by arise from unilineage angioblast precursors and not from nuclear extrusion. Unlike definitive erythroblasts, primi- hemangioblasts [14,15]. Thus, it is likely that all hema- tive erythroblasts do not enucleate spontaneously in vitro topoietic cells, but few endothelial cells, in the mamma- [20]. Nevertheless, they are capable, like definitive lian yolk sac arise from hemangioblast precursors. erythroblasts, of physically interacting with F4/80- positive macrophage cells in vitro,inpartthrougha4- integrin-mediated interactions [20,23]. These findings, Terminal maturation of primitive erythroid supported also by immunohistochemical studies [20], cells raise the intriguing likelihood that primitive erythro- Immature primitive erythroblasts in the blood islands of blasts enucleate while associated with macrophage cells the mouse yolk sac begin to circulate at E8.25 coincident in vivo. Figure 1 Enucleation of late-stage erythroblasts leads to the formation of two cells – a reticulocyte and a pyrenocyte n Pyrenocyte n n Reticulocyte Late-stage erythroblast Pyrenocytes lose phosphatidylserine asymmetry and are subsequently phagocytosed by macrophage cells. Reproduced with permission [22]. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Ontogeny of erythropoiesis Palis 157 regulate the adult b-globin genes. Recent reexamination Globin regulation in primitive erythroid cells of primitive as well as definitive erythroid cells in EKLF- Hemoglobin molecules contain globin chains derived both null mouse embryos, however, indicates that EKLF also a b from the -globin and -globin gene loci. Although defini- regulates multiple erythroid-specific genes, including tive erythroid cells in the mouse express a1-globin,
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