Download Ontogeny of erythropoiesis

Ontogeny of erythropoiesis
James Palis
University of Rochester Medical Center, Rochester,
New York, USA
Correspondence to James Palis, MD, University of
Rochester Medical Center, Department of Pediatrics
and Center for Pediatric Biomedical Research, Box
703, 601 Elmwood Ave., Rochester, NY 14642, USA
Tel: +1 585 275 5098; fax: +1 585 276 0232;
e-mail: [email protected]
Current Opinion in Hematology 2008, 15:155–
161
Purpose of review
The present study review examines the current understanding of the ontogeny of
erythropoiesis with a focus on the emergence of the embryonic (primitive) erythroid
lineage and on the similarities and differences between the primitive and the fetal/adult
(definitive) forms of erythroid cell maturation.
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
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
Introduction
The red cells of mammals are unique in the animal
kingdom as they circulate as enucleated cells. In contrast,
the fully mature red cells of birds, amphibians, and fish
remain nucleated [1]. A century ago, examination of
mammalian embryos revealed the presence of distinct
nucleated and enucleated red cells [2]. The continuous
circulation of small, enucleated erythrocytes during fetal
and postnatal life (‘definitive’ erythropoiesis) was distinguished from ‘primitive’ erythropoiesis, characterized by
the transient circulation of large, nucleated red cells that
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,
respectively. As mammalian primitive erythroblasts circulate as nucleated cells and are confined to the embryo,
they have been thought of as a ‘primitive’ form of
erythropoiesis that shares many characteristics with the
nucleated red cells of nonmammalian vertebrates. Exam-
ination of embryonic and fetal blood cell morphology,
however, revealed that primitive red cells undergo a
synchronous wave of maturation in the bloodstream. Four
years ago, it was discovered that late-stage primitive
erythroblasts in the mouse embryo complete their maturation by enucleating and continuing to circulate for
several more days as erythrocytes [3]. The specification
of hematopoiesis in mammalian embryos was discussed
last in Current Opinion in Hematology 3 years ago [4]. Here,
recent insights regarding the ontogeny of erythropoiesis
and the maturation of the primitive and definitive erythroid lineages will be reviewed.
Emergence of primitive erythropoiesis in the
early embryo
The initial generation of erythroid cells in the embryo
of mammalian and nonmammalian organisms depends
on the formation of mesoderm cells that migrate through
the primitive streak and contribute to the formation of
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156 Erythroid system and its diseases
intraembryonic as well as extraembryonic structures such
as the yolk sac and the placenta in mammals. Immature
primitive erythroid cells rapidly pool into so-called blood
islands soon after the start of gastrulation in the yolk sac of
mammalian and avian embryos [5,6]. These blood islands
become enveloped by endothelial cells, which form the
initial vascular plexus of the yolk sac (reviewed by
Ferkowicz and Yoder, [7]).
The appearance of primitive erythroid cells and endothelial cells at the same time and place within the early
conceptus has long suggested that these lineages share a
common developmental origin. A unique blast colonyforming cell (Blast-CFC) containing both hematopoietic
and endothelial cell potential has been identified in both
cultured embryonic stem cells and mouse embryos [8,9].
Consistent with the hypothesis that the first blood
cells arise from a hemangioblast precursor, clonal studies
reveal that a small number of GATA1-expressing cells in
blood islands of mouse yolk sacs have endothelial as well
as primitive erythroid cell potential [10]. Furthermore,
the transcription factors GATA2 and endoglin, both of
which function in hematopoietic stem cells (HSC), have
each been shown to regulate hemangioblast precursors
[11,12]. The close association of the primitive erythroid
and endothelial lineages is further supported by the
finding that the primitive erythroid lineage in the mouse
emerges from mesodermal cells that express markers
found in adult endothelial cells, including flk-1, vascular
endothelial cadherin, tie-2, and PECAM-1 [13]. There is
an increasing evidence, however, that suggests that
many, if not most, yolk sac vascular cells in the conceptus
arise from unilineage angioblast precursors and not from
hemangioblasts [14,15]. Thus, it is likely that all hematopoietic cells, but few endothelial cells, in the mammalian yolk sac arise from hemangioblast precursors.
Terminal maturation of primitive erythroid
cells
Immature primitive erythroblasts in the blood islands of
the mouse yolk sac begin to circulate at E8.25 coincident
with, or soon after, the onset of cardiac contractions
[16,17]. Over the next 8 days, primitive erythroid cells
mature in a synchronous cohort as they undergo changes
well recognized in maturing definitive erythroid precursors, including a limited number of cell divisions, accumulation of increasing amounts of hemoglobin, nuclear
condensation, a progressive decrease in cell size, and
ultimately enucleation [3,18]. Many of these findings
have recently been confirmed using a transgenic mouse
expressing the enhanced green fluorescent protein
(eGFP) in primitive erythroid cells [19]. Interestingly,
circulating primitive erythroblasts express several adhesion molecules that could mediate interactions with other
cell types [19].
Coincident with primitive erythroblast enucleation, the
appearance of a transient population of very small,
nucleated cells with a rim of ey-globin-positive cytoplasm was noted in the circulation of mouse embryos
[20]. These cells are reminiscent of extruded nuclei
[21], which are the product of enucleation of late-stage
erythroblasts (Fig. 1). The extruded nuclei from definitive erythroid cells undergo rapid loss of the phosphatidylserine asymmetry of the cell membrane and are
engulfed by macrophage cells [22]. As the cell membrane
plays an important role in the biology of these cells,
extruded nucleus is an inadequate term and ‘pyrenocytes’, derived from the Greek word ‘pyren’ (the pit of a
stone fruit), has been proposed as a more appropriate
name for this very transient cell [20]. The discovery of
primitive pyrenocytes in the fetal bloodstream suggests
that late-stage primitive erythroblasts enucleate by
nuclear extrusion. Unlike definitive erythroblasts, primitive erythroblasts do not enucleate spontaneously in vitro
[20]. Nevertheless, they are capable, like definitive
erythroblasts, of physically interacting with F4/80positive macrophage cells in vitro, in part through a4integrin-mediated interactions [20,23]. These findings,
supported also by immunohistochemical studies [20],
raise the intriguing likelihood that primitive erythroblasts enucleate while associated with macrophage cells
in vivo.
Figure 1 Enucleation of late-stage erythroblasts leads to the formation of two cells – a reticulocyte and a pyrenocyte
n
n
Pyrenocyte
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
Globin regulation in primitive erythroid cells
Hemoglobin molecules contain globin chains derived both
from the a-globin and b-globin gene loci. Although definitive erythroid cells in the mouse express a1-globin, a2globin, b1-globin, and b2-globin, primitive erythroid cells
in addition express z-globin, bH1-globin, and ey-globin
[24]. An extensive analysis of globin gene expression in
primitive erythroid cells indicates that the initially
expressed z- and bH1-globin genes are superseded by
the a1-globin, a2-globin and ey-globin genes, respectively, as primitive proerythroblasts at E7.5 transition to
reticulocytes at E15.5 [25]. This ‘maturational’ globin
switching is associated with changes in RNA polymerase
II density at the promoters of these various globin genes.
Furthermore, the bH1-globin and ey-globin genes in
primitive erythroid cells reside in a single large hyperacetylated domain, suggesting that this novel form of globin
switching is regulated by altered transcription factor presence instead of chromatin accessibility [25].
The GATA1 transcription factor plays an essential role in
the regulation of erythroid-specific genes in both primitive and definitive erythroid cells and the loss of GATA1
leads to the arrest of both lineages at the proerythroblast
stage of maturation [26,27]. Interestingly, different functional domains of GATA1 are required for activation of
target genes in primitive versus definitive erythroid cells
[28], suggesting that different transcriptional complexes
may form in these lineages. Recent examination of murine erythroleukemia cells has led to the identification of
novel transcriptional complexes involving a core complex
(GATA1, Tal1, E2A, Lmo2, and Ldbd1) and newly
identified Ldb1-binding partners Eto-2, Cdk9, and
Lmo4 [29]. Forced downregulation of these latter transcription factors in zebrafish embryos reveals functional
roles in definitive, but not primitive, hematopoiesis.
These and other data are leading to increasing complex
models of genetic regulatory networks in the emerging
embryo and definitive erythroid cells [30].
Several transcription factors have been implicated in the
regulation of globin gene expression in primitive erythroid cells, including several Kruppel-like transcription
factors. Studies of klf2-null mouse embryos revealed
significant decreases in bH1-globin and ey-globin transcripts in primitive erythroid precursors [31]. Interestingly, human e-globin transgenes were also reduced in
mice lacking klf2, providing evidence that this transcription factor plays a similar role in humans. Morpholino
knockdown of klf4 in zebrafish embryos leads to
decreased embryonic globin gene expression [32].
Furthermore, klf4 preferentially binds the CACC sites
in the promoters of the embryonic compared with the
adult b-globin genes. The erythroid-specific Kruppellike factor (EKLF) was originally thought to primarily
regulate the adult b-globin genes. Recent reexamination
of primitive as well as definitive erythroid cells in EKLFnull mouse embryos, however, indicates that EKLF also
regulates multiple erythroid-specific genes, including
genes encoding AHSP, heme synthetic pathway proteins
and cytoskeletal proteins such as ankyrin and band
3 [33,34]. Surprisingly, EKLF-null mouse embryos also
have reduced accumulation of bH1-globin and ey-globin
transcripts in primitive erythroblasts [35]. Furthermore,
double EKLF/klf2-null mouse fetuses have a more
severe reduction in embryonic globin gene expression
than either single-null mutant, indicating that these two
Kruppel-like factors play nonredundant roles in embryonic globin gene regulation.
Erythropoietin is the central cytokine necessary for
definitive erythroid cell maturation; however, its role in
primitive erythropoiesis is less well understood. Targeted disruption of erythropoietin in mouse leads to a
significant decrease in primitive erythroid cell numbers,
but maturation does not seem to be disrupted for the
remainder [36,37]. Interestingly, morpholino knockdown
of erythropoietin in zebrafish embryos leads to a similar
differential phenotype between primitive and definitive
erythropoiesis [38]. Examination of erythropoietin signaling revealed several differences in mouse embryonic
stem cell-derived primitive and definitive erythroid cells
[39]. Primitive erythroblasts express higher levels of
erythropoietin receptor and have a sustained and robust
phosphorylation of the downstream STAT5 signaling
molecule but barely detectable levels of the STAT5
inhibitory protein SHP-1. These differences predict a
heightened sensitivity of primitive erythroblasts to erythropoietin signaling. Although these studies suggest that
there may be differential roles for erythropoietin in
primitive versus definitive erythropoiesis, it is likely that
other cytokine signaling cascades differentially regulate
primitive and definitive erythroid cell maturation.
Hematopoiesis in the yolk sac is not confined
to primitive erythropoiesis
Examination of hematopoietic progenitors in carefully
staged mouse embryos as well as cultured embryonic
stem cells has revealed two overlapping waves of erythroid potential [40–42] (Fig. 2). The first wave consists
of primitive erythroid progenitors (EryP-CFC) present in
the yolk sac between E7.25 and E9.0 of gestation that is
temporally associated with macrophage and megakaryocyte progenitors. Recent clonogenic studies in mouse
embryos indicate that the primitive erythroid and megakaryocyte lineages are tied to a common bipotential primitive erythroid/megakaryocyte progenitor [43]. Thus,
primitive hematopoiesis is at least bilineage in nature.
The developmental origin of thrombocytes, however, has
not yet been examined in other model organisms. The
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158 Erythroid system and its diseases
Figure 2 Simplified model of erythroid ontogeny in the mammalian embryo
Current data support a model in which three waves of erythroid progenitors emerge in the mammalian embryo. The first wave consists of primitive
erythroid progenitors (EryP-CFC) that originate in the yolk sac from hemangioblast precursors (HB) and generate a synchronous cohort of primitive
erythroid precursors that mature in the bloodstream and enucleate to form reticulocytes and pyrenocytes. The second wave consists of a transient wave
of definitive erythroid progenitors (BFU-E) that emerge from the yolk sac and seed the fetal liver. There they generate maturing definitive erythroid
precursors that enucleate to become the first circulating definitive erythrocytes (RBC) of the fetus. The third wave consists of a continuous stream of
definitive erythroid progenitors in the late gestation liver and postnatal marrow that originate from adult-repopulating hematopoietic stem cells (HSC).
Unlike primitive erythroid cells, definitive erythroid precursors mature extravascularly within erythroblast islands. AGM, aorta–gonad–mesonephros
region; mf, macrophage cell.
second wave of definitive erythroid progenitors (BFU-E)
emerges and expands in the yolk sac between E8.25 and
E10.5 (see below), and is temporally linked to the expansion of multiple unilineage and multilineage myeloid
progenitors [42].
Emergence of definitive erythroid potential in
the embryo
Primitiveerythroid cells fulfillthefunctionscritical for early
postimplantation embryonic survival and growth, however
the fetus requires even more red cells to meet the demands
of growth at later stages of development. Prior to the
formation of the bone marrow, the liver serves as the site
of maturation of definitive erythroid cells in the mammalian
fetus. The liver in the murine embryo is colonized by
external hematopoietic elements at E9.5, soon after it
begins to form as an organ. BFU-E and CFU-E subsequently expand exponentially in numbers for several
days and generate definitive erythroid cells [44]. The
developmental origin of the BFU-E that initially colonize
the liver has been postulated to be the yolk sac, as BFU-E
first emerge in the yolk sac at E8.25, before the onset of
the circulation, and continue to preferentially expand in
numberswithin theyolk sac forthenext48 h [40,42](Fig.2).
Further evidence in support of the developmental origin
of definitive erythroid potential comes from the mouse
models lacking a functional circulation, as for example, vascular endothelial cadherin-null embryos [45]. A
more recent model involves loss of NCX1, a sodium–
calcium exchanger whose expression is confined to the
heart in the mouse embryo. NCX1-null embryos lack
a heartbeat and thus have no functional circulation, and
yet have normal numbers of primitive and definitive
erythroid progenitors emerging in the yolk sac [46].
Few definitive erythroid progenitors, however, are found
within the embryo proper of these mutant mice, supporting the hypothesis that all definitive hematopoietic progenitors are initially generated in the yolk sac between
E8.25 and E10 and are redistributed to the embryo proper
at the onset of embryonic circulation. The NCX1-mutant
embryo should continue to serve as a useful model to
dissect the emergence of hematopoietic potential within
the embryo proper and the placenta without the confounding factor of blood cell movement within the circulation. In aggregate, these studies indicate that a transient
wave of definitive erythroid progenitors emerges from the
yolk sac of mammalian embryos prior to the emergence of
adult-repopulating hematopoietic stem cells and colonizes the fetal liver (Fig. 2). Interestingly, a wave of
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Ontogeny of erythropoiesis Palis 159
definitive ‘erythro-myeloid’ progenitors has recently
been found in the posterior blood islands of zebrafish
embryos after the appearance of primitive erythroid cells
in the intermediate cell mass but before emergence of
HSC in the region of the aorta [47]. These findings
provide evidence that hematopoietic ontogeny is quite
highly conserved between disparate species.
Toward the end of gestation, definitive erythroid progenitors in the mammalian embryo transition from the liver to
the newly formed bone marrow. Although fundamentally
similar to their adult counterparts, fetal erythroid progenitors also have some distinctive features. First, fetal BFU-E
have a greater and more rapid proliferative capacity. Second, fetal, but not steady-state adult, BFU-E proliferate
in vitro in response to erythropoietin in theabsence of added
colony-stimulating factors [48,49]. Finally, CFU-E in
the murine fetus are more sensitive to erythropoietin [50].
Maturation of definitive erythroid cells
In contrast to primitive erythroid cells that mature in the
bloodstream, definitive erythroid precursors in the fetal
liver and postnatal marrow mature while attached to
macrophage cells of erythroblastic islands [51] (Fig. 2).
Although macrophage cells engulf and digest pyrenocytes
following enucleation [22], it is unclear what other functions macrophage cells perform to enhance erythroid
maturation. It has recently been shown that coculture of
maturing Friend leukemia virus infected erythroid cells
with macrophage cells in vitro enhanced their proliferation
but did not alter their intrinsic ability to enucleate [52].
Potential ‘nurse’ functions of macrophage cells, such as the
provision of iron and cytokines, remain to be proven.
Erythroblast islands bring maturing definitive erythroid
precursors in contact not only with macrophage cells but
also with other erythroblasts. Fas and FasL signaling
between maturing erythroblasts has been invoked as a
mechanism controlling erythroid cell output. Both negative feedback of more mature erythroblasts on immature
erythroblasts as well as autoregulatory loops at the proerythroblast stage of maturation have been proposed
[53,54]. As definitive erythroblasts mature extravascularly, they are also in contact with stromal elements.
Recent evidence suggests that definitive erythroblasts
transition from an erthropoietin-dependent phase to a
fibronectin-dependent phase, and that both erythropoietin
and fibronectin deliver antiapoptotic signals to maturing
erythroblasts [55]. Alpha 4 integrin was shown to mediate
this erythroblast–fibronectin interaction, raising the intriguing question of whether similar signals are mediated to
erythroblasts by VCAM1 on macrophage cells. Surprisingly, erythropoietin was recently shown to play a role at
very late stages of erythroid maturation by specifically
altering the expression of adhesion molecules, including
podocalyxin, and thus regulating reticulocyte egress from
the marrow [56]. These studies highlight an emerging role
for adhesion factors in the terminal differentiation of
definitive erythroid cells.
MicroRNAs are endogenous molecules that target
mRNAs in a sequence-specific manner and regulate
various cellular functions. Recent screens have identified
numerous microRNAs in definitive erythroid cells that
are either upregulated or downregulated with maturation
[57–59]. Initial functional studies in murine erythroleukemia cells indicate that the abundantly expressed miR451 facilitates erythroid maturation [57]. The continued
study of microRNAs and their targets will lead to the
identification of genes critical for hematopoietic differentiation and erythroid lineage maturation throughout
ontogeny.
Human embryonic stem cells serve as a new
model of embryonic erythropoiesis
The culture of human embryonic stem cells has emerged
as an increasingly important model of early embryonic
events. Recent studies indicate that the in-vitro differentiation of human embryonic stem cells recapitulates
hematopoietic ontogeny reminiscent of the in-vivo yolk
sac, including overlapping waves of hemangioblast,
primitive erythroid, and definitive erythroid potential
[60–62]. Interestingly, culture of differentiating human
embryonic stem cells in liquid culture has recently provided evidence that human primitive erythroid cells, like
their murine counterparts, undergo ‘maturational’ z-globin to a-globin switching [63]. Thus, human embryonic
stem cells can provide access to hematopoietic cells that
are not otherwise available for study.
Conclusion
Primitive erythropoiesis serves as a useful model of mammalian erythroid differentiation, as primitive erythroblasts
in mammals mature in a synchronous cohort in the bloodstream and ultimately enucleate. In contrast, definitive
erythroid precursors mature attached to macrophage cells
in erythroblast islands within the complex cellular milieu
of the fetal liver and postnatal bone marrow (Fig. 2).
Erythroblastic islands can thus facilitate erythroblast–
erythroblast and erythroblast–stromal interactions that
play important roles in the regulation of definitive erythropoiesis. The continued study of 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.
The comparative investigation of embryonic development
in multiple model organisms, including mouse, chicken,
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160 Erythroid system and its diseases
Xenopus and zebrafish, will continue to provide important
insights into the ontogeny of erythropoiesis. The in-vitro
culture of human embryonic system cells is now established as an important model system to investigate the
early ontogeny of human hematopoiesis and offers the
potential for cell-based therapies for the treatment of
hematopoietic disorders.
Acknowledgements
I thank coworkers and colleagues for many stimulating discussions.
This study was supported in part by the National Institutes of Health
grants DK09361 and DK071116.
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