Hematology

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Regulation of erythropoiesis: emerging concepts

and therapeutic implications

Pu Tang & Huaquan Wang

To cite this article: Pu Tang & Huaquan Wang (2023) Regulation of erythropoiesis:
emerging concepts and therapeutic implications, Hematology, 28:1, 2250645, DOI:
10.1080/16078454.2023.2250645

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HEMATOLOGY
2023, VOL. 28, NO. 1, 2250645
https://doi.org/10.1080/16078454.2023.2250645

REVIEW ARTICLE

Regulation of erythropoiesis: emerging concepts and therapeutic implications

Pu Tang and Huaquan Wang
Department of Hematology, General Hospital, Tianjin Medical University, Tianjin, People’s Republic of China

ABSTRACT ARTICLE HISTORY

The process of erythropoiesis is complex and involves the transfer of cells from the yolk sac to Received 19 April 2023
the fetal hepar and, ultimately, to the bone marrow during embryonic development. Within the Accepted 17 August 2023
bone marrow, erythroid progenitor cells undergo several stages to generate reticulocytes that
KEYWORDS
enter the bloodstream. Erythropoiesis is regulated by various factors, with erythropoietin (EPO) Erythropoiesis; embryonic
synthesized by the kidney being the promoting factor and hepcidin synthesized by the hepar erythropoiesis; human
inhibiting iron mobilization. Transcription factors, such as GATA and KLF, also play a crucial role erythropoietin (EPO);
in erythropoiesis. Disruption of any of these factors can lead to abnormal erythropoiesis, erythroferrone (ERFE);
resulting in red cell excess, red cell deficiency, or abnormal morphological function. This ferritin; transferrin; anemia;
review provides a general description of erythropoiesis, as well as its regulation, highlighting polycythemia
the significance of understanding the process for the diagnosis and treatment of various
hematological disorders.

Introduction absorbed during development [3]. Blood islands,

Erythropoiesis is a process by which red blood cells
(erythrocytes) are produced in the marrow. It involves
the differentiation of erythroid progenitor cells into
mature RBCs, which transport oxygen from the lungs
to the body’s tissues. erythropoiesis is a complex
process that is strictly regulated by varieties of
factors, including hormones, cytokines, and growth
factors.
In recent years, there have been vital advances in
our awareness of the molecular mechanisms that
govern erythropoiesis. These advances have led to
the positive result of new therapeutic strategies for
the treatment of erythropoietic disorders. In the
article, we review the issues of embryonic erythropoi-
esis, the cytokines involved in erythropoiesis, signaling
cascades, and possible problems in erythropoiesis.
The normal physiological course of
erythropoiesis
Erythropoiesis in embryos
In embryos, erythropoiesis occurs in a different
location than in adults. During embryonic develop-
ment, erythropoiesis initially takes place in the yolk
sac, and later shifts to the hepar and spleen, before
ultimately transitioning to the marrow [1].
The Yolk sac is the original site of erythropoiesis
during the first few weeks of embryonic development
[2], and it’s a short-lived membrane which is gradually
which contain primitive erythroid progenitor cells,
form in the mesoderm layer of the yolk sac. These pro-
genitor cells differentiate into erythroblasts, which
produce embryonic hemoglobin (α2ε2) [4]. α2ε2 is
composed of a pair of alpha and a pair of epsilon
globin chains and has a stronger affinity for oxygen
than adult hemoglobin.
Around 6–8 weeks of gestation, erythropoiesis shifts
to the hepar and spleen [5], as these organs become
capable of producing erythropoietin (EPO), the
hormone that stimulates erythropoiesis. Studies show
that EMP produced in the mouse yolk sac migrates
to the hepar and colonizes [6], and hematopoietic
stem cells also migrate to the hepar [7]. The hepar
becomes the primary site of erythropoiesis from
around weeks 10–28 of gestation, while the spleen
mainly produces RBCs in the second trimester.
By the end of the second trimester, erythropoiesis
begins to shift to the marrow, which becomes the
initial site of erythropoiesis by the time of birth
(Figure 1). At this stage, fetal hemoglobin (HbF) is the
primary type of hemoglobin produced, which pos-
sesses a stronger affinity for oxygen than adult hemo-
globin (HbA) and helps to facilitate oxygen transport
across the placenta. After birth, the output of HbF
gradually decreases and is replaced by the output of
HbA.
Fetal hematopoiesis is regulated by multiple factors.
For example, ferritin IRP2 regulates iron infusion from
the maternal placenta [8], and EpoR can lengthen the

CONTACT Huaquan Wang wanghuaquan@tmu.edu.cn

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrest-
ricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the
Accepted Manuscript in a repository by the author(s) or with their consent.
2 P. TANG AND H. WANG

Figure 1. An overview of erythropoiesis in the embryo. Erythropoiesis in the embryo can be divided into three stages. The first
stage is the third to sixth week of embryogenesis, during which the yolk sac, formed by mesodermal cells and angioplastic cells,
produces platelets, PEs, and macrophages, with the erythrocyte-containing PEs entering the circulation. The second stage is the
third to sixth month of embryonic development, during which EMPs produced by the yolk sac migrate to the liver and proliferate
and differentiate into red cells in the liver. The third stage is after six months of embryonic development, during which the hema-
topoietic center is located in the bone marrow, and hematopoietic stem cells differentiate into red cells and enter the circulation.

early stages of the erythrocyte cycle by increasing red
cell cycle length [9]. Furthermore, growth factors (SCF)
are critical for erythropoiesis and are critical for main-
taining normal adult erythrocyte numbers [10].
Erythropoiesis first occurs in the yolk sac, then metas-
tasizes to the fetal liver, and finally resides in the bone
marrow after birth. Switching between these sites is
associated with changes in globin expression and
oxygen-binding affinity of erythrocytes. When erythro-
cyte proliferation metastasizes from the yolk sac to the
fetal liver, a primordial to final erythroblastic transform-
ation occurs. Fetal to adult globin conversion occurs
when erythropoiesis is transferred from the fetal liver
to the bone marrow. Fetal globin has a higher oxygen
affinity than adult globin and can better extract
oxygen from maternal blood. These spatial and tem-
poral switches during erythropoiesis allow the develop-
ing embryo/fetus to adapt to the changing oxygen
requirements during development [2].
Erythropoiesis in bone marrow
Erythropoiesis in bone marrow is the process by which
progenitor cells become mature red blood cells (RBCs),
about 20 billion erythrocytes emerge in the marrow
every day [11]. This course is regulated and controlled
by a heterogeneous network of signaling pathways
and transcription factors.
In the bone marrow, erythroid progenitor cells
differentiate into erythroblasts, which undergo
several rounds of cell division and synthesis of hemo-
globin, the protein that brings oxygen in RBCs. The
cells gradually reduce their size and nucleus, and
increase their cytoplasmic volume, ultimately becom-
ing reticulocytes.
The output of erythroblasts is regulated by a
number of cytokines and growth factors, including ery-
thropoietin (EPO), stem cell factor (SCF), and interleu-
kin-3 (IL-3), among others. EPO, which is produced
primarily by the kidneys in response to low oxygen
levels in the body, excites the differentiation and pro-
liferation of erythroid progenitor cells.
The process of erythropoiesis in the bone marrow is
also affected by the microenvironment, or niche, in
which the cells remain. This niche consists of various
cell types, containing osteoblasts, endothelial cells,
stromal cells, as well as extracellular matrix com-
ponents [12].
Osteoblasts, which are bone-forming cells, have
been shown to regulate erythropoiesis through the
output of cytokines and growth factors, as well as
direct cell-to-cell contacts with erythroid progenitor
cells. Endothelial cells also play a role in regulating ery-
thropoiesis by producing cytokines and growth
factors, and by providing a source of oxygen and
other nutrients. Stromal cells, which are mesenchymal

cells that support hematopoiesis, also contribute to
the regulation of erythropoiesis by producing growth
factors and providing a supportive niche for erythroid
progenitor cells (Figure 2).
Terminal enucleation is the process by which the
nucleus is extruded from late erythrocytes before
they mature into reticular cells. This is a unique
feature of mammalian erythrocyte production [13].
Some congenital dysplasia of erythropoietic anemia
(CDAs) and myelodysplastic syndrome (MDS) may
have a pathological phenomenon of erythrocyte enu-
cleation disorder. In MDS, abnormal erythrocyte
islands and poor erythrocyte segregation may indi-
cate impaired peripheral enucleation. In CDA type I,
caused by CDAN1 or C15orf41 mutations, the
encoded proteins are thought to have roles in chro-
matin remodeling during nuclear extrusion. In CDA
type II caused by SEC23B mutations, SEC23B may
be involved in mesomeric formation during cell div-
ision, and its dysfunction can lead to impaired enu-
cleation [14]. In CDA type III, caused by a KIF23
mutation, the mutant protein disrupts cytokinesis
through effects on the mitotic spindle apparatus. In
these cases, the molecular mechanisms of impaired
enucleation are not fully understood, but may
involve protein dysfunction involved in the regu-
lation of chromatin remodeling, cell division, and
erythrocyte island formation.
Erythroblast island
Erythroblast island refers to a unique microenviron-
ment in the marrow where erythroblasts, the precur-
sors of erythrocytes, interact with macrophages. The
erythroblast island is symbolized by a central macro-
phage surrounded by a circle of developing
erythroblasts.
Macrophages within the erythroblast island play an
important role in supporting erythropoiesis, the course
by which progenitor cells differentiate into mature
erythrocytes. Macrophages provide various factors
such as transferrin, iron, cytokines, and growth
factors to support erythropoiesis [12].
The erythroblasts in the erythroblast island depend
on the macrophages for survival and differentiation.
Macrophages provide adhesion molecules and phago-
cytose the extruded nuclei and organelles from eryth-
roblasts. Additionally, macrophages produce growth
factors and cytokines like erythropoietin, stem cell
factor, and insulin-like growth factor-1, which
promote erythropoiesis and the proliferation of
erythroblasts.
The close association between macrophages and
erythroblasts within the erythroblast island creates a
supportive microenvironment that stimulates the
efficient output of functional erythrocytes. Dysfunction
or disruption of this microenvironment can lead to
HEMATOLOGY 3
impaired erythropoiesis and anemia. Stress erythropoi-
esis is highly dependent on signals such as EPO/EPOR/
JAK2/STAT5, as well as activation signals in erythroid
islets such as BMP4/SMAD5 and integrin signals [15].
Stages of RBC maturation and differentiation
Erythropoiesis is a multi-stage process that typically
lasts for approximately 14 days. It includes the
differentiation of hematopoietic stem cells into ery-
throid progenitor cells and megakaryocytes. Ery-
throid progenitor cells consist of erythroid bursting
forming units (BFU-E) and erythroid colony forming
units (CFU-E), which are a continuous stage of ery-
throid progenitor cells [16]. These cells then differ-
entiate into erythroid precursors of varying
morphologies.
The earliest recognizable erythroid precursor cells
are pro-erythroblasts (pro-E), which mark the begin-
ning of the second stage of red blood cell (RBC) matu-
ration. Pro-E cells develop into basophilic (Bas-E),
polychromatic (Poly-E), and orthochromatic erythro-
cytes (Ortho-E) in a sequential manner, ultimately
leading to the formation of reticulocytes that lack a
nucleus [17]. During this process, the size of the cells
and nuclei gradually decreases while the accumulation
of hemoglobin increases [1].
Late-stage erythropoiesis is characterized by the
loss of the nucleus, loss of surface biomarkers, and
the formation of a strong and extendable cytoskeleton.
These changes allow for the final maturation and
differentiation of erythroid precursors to fully mature
erythrocytes [18].
Biomarkers of erythropoiesis
Studies utilizing single-cell genomics have demon-
strated that the output of erythrocytes (RBCs) is an
ongoing process characterized by varying cellular
states and the expression of different genes [16].
The progenitor cells, BFU-E and CFU-E, are highly
enriched in the umbilical cord and bone marrow
as well as peripheral blood, as indicated by the
expression of CD34, CD105, CD36, CD71, and
CD45RA markers. By using CD34/CD105 and GPA/
CD105 spectra, all four progenitor stages and five
terminal erythroid differentiation stages can be
identified [19].
Further differentiation of human erythroid precur-
sors can be classified by surface expression of the
transferrin receptor (CD71) and glycoprotein A
(CD235a). Additionally, the expression of Integrin
α4 (CD49D) and band three protein has been
found to promote the resolution of multifarious
stages of erythroid precursor differentiation [1]. A
combination of GYPA (CD235A) and CD105
expression or the gain of band3/SLC4A1 (CD233)
4 P. TANG AND H. WANG

Figure 2. An overview of erythropoiesis in the bone marrow. The formation of reticulocytes from hematopoietic stem cells (HSPC)
in the bone marrow takes about seven steps. During the first stage of erythropoiesis, hematopoietic stem cells produce mega-
karyocytes in addition to erythroid bursting-forming units (BFU-E)and erythroid colony-forming units(CFU-E). The second stage
of erythropoiesis is marked by the production of proerythroblasts (Pro-E), the first erythroid cells to be morphologically recogniz-
able. The pro-E then produces basophils (Bas-E), which cease to produce ribosomes during basophilization. Bas-E subsequently
produces polychromic phage (Poly-E), Poly-E subsequently produces positively stained erythrocytes (Ortho-E), and Ortho-E even-
tually produces reticulocytes. During erythropoiesis, the size of the cells decreases continuously, and the intracellular hemoglobin
content gradually increases.

expression and loss of CD49d can be used to track
erythroid maturation [16].
Biomarkers of erythropoiesis in human and mouse
is totally different. In humans, miR-451 and miR-144
are highly expressed during erythropoiesis and play
an important role in promoting erythrocyte differen-
tiation. They are located in the same gene cluster
and are regulated by the red transcription factor
GATA1. miR-486 is also upregulated during erythropoi-
esis and collaborates with GATA1 as a regulator of
erythrocyte differentiation. miR-221 and miR-222 are
down-regulated during the differentiation of human
hematopoietic progenitor cells into red blood cells.
miR-320 is associated with the expression of CD71
protein, a marker of reticular cell maturation in
human sickle cell anemia. CD71 and CD36 in early pro-
genitor cells, glycoprotein A in late progenitor cells/
precursors, and CD235a in mature red blood cells are
key markers of human erythropoiesis.
In mice, as in humans, miR-451 and miR-144 are
key red blood cell biomarkers in mice that promote
erythropoiesis when overexpressed. miR-150 is
down-regulated during erythrocyte terminal differen-
tiation in mice. miR-221, miR-222 and miR-223 were
down-regulated during erythropoiesis in mice. let-7
miRNA is upregulated during mouse erythrocyte
maturation [20]. In mice, Ter119, CD71, and HE4
are markers of progenitor cells and erythrocytes,
and Ter119 is a marker of mature red blood cells.
In addition to EPO, SCF and IL-3 are key cytokines
that regulate early erythrocyte production in mice.
Similar to humans, TGF-β signaling also negatively
regulates late erythropoiesis in mice. Transcription
factors such as GATA-1 and KLF1 are key mouse ery-
throid regulators [21].
Regulatory mechanisms of erythropoiesis
Exogenous regulation and control of
erythropoiesis
Varieties of external elements can activate essential
downstream signaling pathways that regulate the
differentiation, proliferation, and survival of erythro-
cytes. One such factor is IL-3, which can stimulate the
proliferation of early progenitors, containing BFU-E.
Additionally, KIT ligands can bind to KIT (CD117), pro-
moting the proliferation of BFU-E, CFU-E, and erythro-
blasts [16].
Wnt signaling also plays a part in the regulation of
erythropoiesis, particularly in the terminal differen-
tiation of erythrocytes in myeloid sinusoidal

endothelial cells, as well as in the maturity of reticulo-
cytes and the overall function of red blood cells and
hematopoietic cells in mesenchymal stromal cell popu-
lations [22].
Regulation of erythropoiesis by EPO
EPO is a glycoprotein that plays a crucial role in adjust-
ing erythrocyte quality and hematopoiesis in transloca-
tion and formation of erythrocyte transcriptional
programs [11]. During stress erythropoiesis, EPO
quickly improves the appearance of the anti-apoptotic
regulator BCL-XL in early erythrocytes by STAT5 and
inhibits the pro-apoptotic proteins BIMsponse to alter-
nations in tissue oxygenation [23]. EPO is produced by
renal stromal cells in adults and mainly by the hepar in
embryos. EPO contributes to hematopoiesis of hema-
topoietic stem and progenitor cells (HSPC) by promot-
ing erythroid proliferation and survival from CFU-E,
which rapidly decreases with the terminal maturation
of the cell [16].
EPO induces erythropoiesis by binding to EPO
receptor (EPOR) on precursors of erythroid cells in
the marrow, promoting their survival, proliferation,
and differentiation. EPOR is expressed primarily on
CFU-E, erythrocytes, and early basophils. Binding to
EPO prevents apoptosis of these erythroid progenitors
[24].
The EPO/EPOR pathway stimulates erythroid devel-
opment by activating the JAK2/STAT3/STAT5 pathway,
which aids in Nucl, NOXA, Fas, and FasL [25]. EPO also
stimulates erythroid precursor cells in the marrow and
spleen to quickly produce erythroferrone (ERFE) by
STAT5 [26].
Activation of STAT3 by EPO/EPO receptors leads to
increased expression of genes involved in red blood
cell progenitor cell survival (Bcl-xL), proliferation, and
differentiation. A key target of STAT3 is the transcrip-
tion factor GATA-1, which regulates the expression of
many red blood-cell specific genes, including those
involved in hemoglobin production. STAT3 is rigidly
and briefly regulated during erythropoiesis through
EPO-mediated JAK2 activation, followed by rapid feed-
back inhibition through SOCS protein, phosphatase,
and proteasome degradation to prevent overactivity.
This allows STAT3 to induce erythroid gene expression
in a precise manner to match the physiological require-
ments of red blood cell production [11].
JAK2 inactivation leads to anemia, whereas JAK2
mutations lead to raised erythrocyte quantity and ery-
throcytosis. EPO and EPOR play critical roles in erythro-
cyte quality control, and their dysregulation can result
in various hematological disorders.
During hypoxia, the highly conserved hypoxia-indu-
cible factor (HIF) signaling pathway is activated, and
the first target of HIF is EPO. EPO levels increase by
HEMATOLOGY 5
1000-fold in response to tissue hypoxia. In mice,
HIF2a specifically activates EPO, which is required for
EPO expression in the kidney and hepar. Destruction
of HIF2a leads to anemia and hematopoietic defects.
EPO binds to EPOR in the hepar and inhibits the
expression of hepcidin, which can also be inhibited
by EPO-derived factors [27]. Osteoblasts can also gen-
erate EPO to promote erythropoiesis under stable con-
ditions of constitutive HIF. Exogenous EPO and the
formation of bone have a connection with raised
bone marrow vascular density and angiogenesis in
many repair models. EPO directly stimulates osteogen-
esis by targeting mesenchymal stromal cells and
hematopoietic stem cells, and indirectly stimulates
osteoblast differentiation by irritating HSCs to secrete
bone morphogenetic proteins. EPO also directly stimu-
lates osteoblast differentiation toward mature osteo-
clasts via Jak2 and PI3K pathways, resulting in an
according decline in EPOR transcript levels [11]
(Figure 3).
Regulation of erythropoiesis and iron
metabolism by the ERFE-ferritin-transferritin
axis
The regulation of iron metabolism and erythropoiesis
is crucial, and it also involves the ERFE-ferritin-trans-
ferrin axis [16]. Approximately two-thirds of the
body’s iron is stored in RBCs [28]. RBCs require 20–
25 mg of iron daily, which is supplied by iron trans-
port proteins that contain only 3 milligrams of iron at
any given moment and are replaced every several
hours [29]. Since the human body cannot excrete
iron, the balance between iron intake, transport, util-
ization, and storage must be tightly regulated [30].
Iron required by RBCs is obtained largely from
macrophages phagocytosing old RBCs, and is sup-
plied daily by 20–25 mg of iron, which is absorbed
in the intestine by 1–2 mg (0.05% of total iron
content in the body) to make up the iron loss due
to intestinal epithelial cell loss and a small amount
of blood loss in the skin [31].
Non-heme iron can be absorbed from the lumen by
the divalent metal transport protein 1 (DMT1) located
at the apical surface of epithelial cells in the duodenum
by the duodenal cytochrome B reductase (DCYTB),
which reduces iron to ferrous metal, and heme iron
is absorbed more efficiently in the gut than non-
heme iron [32]. Absorbed iron can be utilized by intes-
tinal cells, kept in ferritin, or transported to the circula-
tion by iron a basolateral membrane of the intestinal
cells [33]. Iron absorption and tissue distribution are
regulated mainly by the interaction of the hepar hor-
mones hepcidin and ferritin. Ferritin exerts its function
through three common forms: ferritin coordinated by
the side chains of proteins, ferritin in the heme loop,
and ferritin in the iron-sul cluster. The iron homeostasis
6 P. TANG AND H. WANG

Figure 3. An overview of the mechanism by which EPO regulates erythropoiesis. Hypoxia-inducible factor 2 (HIF-2) induces EPO
production, which in combination with EPOR activates MAPK, JAK2, and PI3K signaling and directly inhibits the expression of hep-
cidin. JAK2 subsequently activated both STAT3 and STAT5 signaling, in which STAT5 activated erythroid receptor (ERFE) and anti-
apoptotic regulator BCL-XL, promoting the development of nuclear translocation NRD. Stat5 also inhibited BIM, NOXA, Fas, and
FasL.

system is mainly affected by erythrocytes (erythrocytes
and their precursors in erythropoiesis-producing
organs), two storage locations (hepatocytes in the
hepar, macrophages in the spleen and hepar),
plasma transporting iron between tissues and organs,
and absorptive intestinal cells in the duodenum [34].
Erythroferrone (ERFE) is a protein synthesized and
secreted by red blood cells in the marrow and
extramedullary regions, and is induced by EPO
output. ERFE belongs to the C1Q tumor necrosis
factor-related protein family, and acts directly in
the hepar to decrease hepcidin expression. Unlike
EPO, which can stimulate erythropoiesis in both
stress and homeostatic conditions, ERFE only
responds to stress erythropoiesis. ERFE inhibits hep-
cidin expression, increases the supply of iron, and
helps maintain iron balance during periods of high
erythropoietic demand [26].
Ferritin is synthesized in the hepar and upon
binding to iron, it undergoes ubiquitination and gets
degraded in the lysosomes. This process reduces the
transfer of ferritin to the cell membrane, keeps iron
inside the cell, and lowers the amount of iron in the
blood. The regulation of ferritin by endocytosis is
similar to general ligand-induced endocytosis in vivo.
This process is triggered by transporter conformational
changes induced by ferritin, leading to ubiquitin of the
lysine-rich cytoplasmic fraction that links the two six-
helix regions of ferritin. Ferritin is then targeted for
lysosomal and proteasomal degradation through ubi-
quitination, which is facilitated by Rnf217, an impor-
tant E3 ubiquitin ligase [26,34].
Hepcidin is regulated by various factors including
plasma iron concentration (majorly relying on the
contact of ferritin with the transferrin receptors TFR1
and TFR2), hepar iron reserve, systemic inflammation
signals transmitted majorly by IL-6 to hepatocytes,
and erythroid activity signals transmitted mainly
through ERFE concentration [34]. Excessive iron can
be toxic and cause oxidative DNA damage [35], and
in patients with iron overload, hepcidin levels are elev-
ated. The combination of hepcidin and ferritin results
in the rapid degradation of hepcidin. When systemic
iron levels are low, this results in decreased expression
of hepcidin and raised iron mobilization. Hypoxia inhi-
bits hepcidin expression, and the hypoxia-induced
hepcidin inhibition, unrelated to EPO and erythrocyte
output, is mediated by hypoxia-mediated degradation

of C/EBPA, a key transcription factor required for hep-
cidin basal expression. Hepar hypoxia is a strong
inhibitor of hepcidin expression during hepar inflam-
mation and IL-6 output. HIF has a hand in the suppres-
sion of hepcidin, and animal studies have shown that
HIF activation in the mouse hepar decreases hepcidin
expression and increases ferritin in the intestine and
macrophages [27]. Stressful and ineffective erythropoi-
esis can also inhibit ferritin. GDF15 and TWSG1,
members of the transforming growth factor B super-
family, are considered to be pathological inhibitors of
hepcidin in ineffective erythropoiesis., GDF15 and
TWSG1 inhibit hepcidin expression [26] (Figure 4).
HIF2α is activated in the intestine when there are
low levels of iron in the epithelium, leading to an
increase in hepcidin-mediated degradation of ferritin.
During iron deficiency, PHD activity is reduced, which
further enhances the expression of HIF2α. Although
intestinal iron levels do not change during erythropoi-
esis, the decreased oxygen levels in the intestine result
in HIF2α activation. Hepcidin exhibits bacteriostatic
effects on several bacteria and fungi [27].
The transferrin (Tf) complex consists of two lobes,
each of which can bind one iron atom. The degree of
Tf saturation reports the body’s iron capacity, which
is typically between 20% and 45% in healthy human
beings [36]. Transferrin is the only iron transport
protein known so far. Stable transferrin binding to
the cell membrane stimulates iron absorption by the
duodenum, enhances iron recovery by macrophages
from old red blood cells and other cells, and allows
the transfer of iron contained in the hepar [26]. Most
transferrin molecules are bound with hepcidin most
of the time, and this mechanism is quickly adjustable
when the concentration of hepcidin is reduced. In
Figure 4. Mechanism of the action of hepcidin. Various systemic factors regulate the expression of hepcidin. Plasma iron levels
and liver iron reserve levels are factors promoting ferritin expression. In contrast, systemic hypoxia, low iron levels, high IL-6 levels
in the inflammatory state, and HIF and ERFE were inhibitory factors of hepcidin. Ferritin can cooperate with the E3 ubiquitin ligase
Rnf217 for ubiquitylation and degradation of ferritin.
HEMATOLOGY 7
addition to hepcidin, inflammatory stimulation in the
form of Toll-like receptor ligands straightly inhibits cel-
lular ferritin mRNA quantity and reduces cellular
plasma iron output [34].
The transferrin (Tf) complex binds one iron mol-
ecule and has two receptors, TFR1 and TFR2. TFR1
mediates the internalization of Tf in the iron-transfer
pathway, and it can bind partially saturated transferri-
tin, as well as iron in both the light and heavy chains of
ferritin. The affinity of TFR1 for c-valve and n-valve
saturated transferritin is only 5 and 6 times that of
Apo-Tf, respectively. At physiological pH levels, Tf is
discharged from TFR1 to the serum, where it can
combine with iron again [37]. The IRE/IRP system
increases TFR1 expression. The IRE/IRP system func-
tions to regulate cellular iron homeostasis, ensuring
that cells can increase TfR1 expression when the iron
supply is insufficient, thereby enhancing iron absorp-
tion and utilization efficiency. Once the cellular iron
level reaches an appropriate level, IRP dissociates
from the IRE, leading to a decrease in TfR1 expression
to prevent excessive iron uptake. When the cellular
iron level is low, IRP binds to the IRE (iron-responsive
element) located in the 3′ UTR (untranslated region)
of TfR1 mRNA, stabilizing its structure and promoting
the stability and translation of TfR1 mRNA. As a
result, the expression level of TfR1 increases, allowing
cells to more effectively uptake iron [38]. TFR1 is over-
expressed in differentiated erythroid cells. Nuclear
endosomes including Holo-Tf-TFR1 approach the mito-
chondria and transfer iron to the organelle by rapid
and transient contact with the mitochondria, restrain-
ing the cytoplasmic iron pool without triggering the
adjustment of the IR/IRP system [36].
8 P. TANG AND H. WANG
Tfr2 is a transmembrane glycoprotein that acts as a
receptor for circulating iron. It’s similar to the classical
transferrin receptor Tfr1. Tfr2 plays an important part in
regulating iron homeostasis by controlling hepcidin
levels. Loss-of-function mutations in Tfr2 result in low
levels of hepcidin, excess circulating iron, and hemo-
chromatosis [39], while mutations in hepcidin cause
severe hereditary iron overload [40].
Unlike TFR1, TFR2 is not adjusted by the IR/IRP
system. TFR2 expression is instead regulated post-
translationally by its ligand, Holo-Tf [36]. TFR2 protects
ferrous plasma Tf from lysosomal degradation and is a
part of the erythroid progenitor EpoR complex, critical
for valid transfer of EpoR to the cell surface and final
differentiation.
Hepatic TfR2 stimulates iron signaling to ferritin
to repress further iron influx into the blood when
iron is present. In contrast, erythroid TfR2 limits
Epo sensitivity to prevent overdose erythropoiesis.
Under iron-deficient conditions, TfR2 becomes
unstable, leading to hepatic TfR2 downregulation,
which inhibits iron signaling to ferritin, stimulates
cellular iron excretion, and increases iron supply to
RBC. Reduction of erythroid TfR2 promotes Epo’s
sensitivity to erythropoiesis and contributes to the
suppression of hepcidin by ERFE [41].
Transcriptional control of erythropoiesis
RBC output is regulated by intrinsic transcription
factors that regulate the differentiation of erythroid
cells. Among these transcription factors, GATA1 plays
an important part in directing the differentiation of
erythroid cells towards RBC lineage. Another key tran-
scription factor involved in RBC output is KLF1.
Mutations in GATA1 and KLF1 are associated with
various types of anemia in humans [1]. These transcrip-
tion factors activate and suppress regulatory networks
involved in RBC output and have different functions in
this process [16].
Transcriptional regulation of GATA in
erythropoiesis
The GATA transcription factor, which contains zinc-
finger DNA binding domains, is critical for various bio-
logical processes, including hematopoiesis [42]. GATA
factors interact with specific regulatory elements to
mediate transcriptional changes [43]. GATA-1 is essen-
tial for the existence and differentiation of progenitors
of red blood cells, while GATA-2 adjusts the survival
and proliferation of hematopoietic stem and progeni-
tor cells [12]. GATA1 has three functional domains,
including an N-terminal activation domain and two
homologous Zn finger domains located in the C-term-
inal region [44]. Various cofactors, such as FOG-1/
ZFPM1, nuclear remodeling bodies, and deacetylase
(NURD) complexes, promote the binding of GATA1 to
regulatory sites [16].
During erythroid cell development, GATA factor
switching occurs, whereby GATA2 protein levels are
decreased and GATA1 protein levels are raised.
GATA1 targets several genes that are regulated by
GATA2 in hematopoietic stem and progenitor cells
[43]. In erythroid cells, GATA1 occupies both the pro-
moter and enhancer, but the enhancer activity
decreases during differentiation, with GATA1 predomi-
nantly binding to the promoter. Enhancers play a more
significant role in the early stages of cell differentiation,
while promoters are more critical in the terminal
stages.
In mouse erythroid progenitors, the GATA2 tran-
scription factor increases the production of the stem
cell cytokine receptor KIT, while GATA1 is responsible
for reducing KIT expression to promote terminal differ-
entiation. However, in human erythroid progenitors,
high levels of KIT expression require GATA1 binding
on erythroid-specific SE.
GATA1 is regulated by various factors at the post-
transcriptional level. HSP27 and HSP70 members of
the heat shock protein family, along with ribosomal
proteins, promote the ubiquitination and proteaso-
mal degradation of GATA1. HSP70 also plays a role
in preventing the caspase-3-mediated intranuclear
division of GATA1, while ribosomal proteins regulate
the normal translation of GATA1 [45]. Additionally,
there is an interaction between GATA1 and p53,
which inhibits RNA Pol I transcription by restricting
the RNA Pol I complex from assembling on the
rDNA facilitator. In cancer, the loss of function of
p53 and mass output of ribosomes may lead to
the inhibition of GATA1 by p53 [17]. On the other
hand, downregulation of p19INK4d reduces GATA1
protein levels and impairs human terminal erythroid
differentiation, which is adjusted by the p-ERK-
HSP70-GATA1 pathway, where PEBP1 serves as a
connection between p19INK4d and the p-ERK-
HSP70-GATA1 pathway [45].
Transcriptional regulation of KLF1 in
erythropoiesis
KLF1 is a protein that is abundant in erythroid cells and
contains three C2H2 zinc fingers at its C-terminus. It
connects its DNA consensus sequence (5′ ccmcrcccn)
mainly in the distal regulatory region, and is expressed
in both primitive and nucleated erythrocytes within
the hematopoietic compartment [46]. Its primary role
in erythropoiesis is the activation of gene transcription,
and it inhibits the differentiation of megakaryocytes
while promoting early differentiation of RBCs [47].
KLF1 plays an important part in the final stages of
the cell cycle and chromatin condensation, which
stimulate RBC output. In the absence of KLF1, RBC

denuclearization is impaired, CDKN2C and CDKN1A
levels are reduced, and RBC proliferation is raised.
Although KLF1 is predominantly a transcriptional acti-
vator, it can also act as a transcriptional inhibitor [16].
Coactivator-coinhibitory interactions under KLF1
acetylation dynamically regulate downstream tran-
scriptional effects [47].
Transcriptional regulation of erythropoiesis by
other factors
TGF-beta is a crucial factor in cell differentiation and
has significant effects on hematopoiesis [48]. TGFβ1
is involved in cell survival, proliferation, and differen-
tiation. Megakaryocytes are the primary source of
TGFβ1 in the bone marrow, but they can also be syn-
thesized by immune cells, macrophages, and marrow
stromal cells. TGFβ1 inhibits early progenitor cell pro-
liferation and stimulates erythroid terminal differen-
tiation through Smad2/3-Smad4 or tiff-1g signaling.
Dysregulation of TGFβ1 may lead to myelofibrosis,
while blocking it may result in the proliferation of ery-
throid progenitors [49]. Additionally, members of the
TGFβ family promote the degradation of HIF1α by inhi-
biting VHL, an E3 ubiquitin ligase, which enhances
hypoxia responses [50].
Unusual and common erythropoietic
disorders
Anemia is a condition characterized by a hemoglobin
level below 13 g/dL in adult males and below 12 g/
dL in non-pregnant females [51], and can result from
decreased erythropoiesis, excessive red blood cell
destruction, or blood loss [52]. Reduced erythropoiesis
can be sorted into several categories, including anemia
caused by abnormalities in hematopoietic stem cells
(e.g. aplastic anemia, PRCA, myelodysplastic syndrome,
leukemia), abnormalities in hematopoietic regulation
(e.g. myeloid necrosis, myelofibrosis, tumor disease,
myeloid metastasis, bone marrow stromal-cell-
involved diseases), hyperlymphocyte dysfunction (e.g.
AA and immune-associated pancytopenia), abnormal-
ities in hematopoietic regulatory factors (e.g. chronic
disease-associated anemia), hyperapoptosis (e.g. par-
oxysmal nocturnal hemoglobinuria), or deficiency of
hematopoietic materials (e.g. iron-deficiency anemia,
deficiency of iron, leucine, and vitamin B12, and mega-
loblastic anemia) [53]. Additionally, low levels of sel-
enium, which is involved in redox reactions by
binding to the selenium family of cysteine-containing
proteins and has an antioxidant effect, can lead to
reduced erythroid cell number and differentiation
under stress, resulting in an ineffective response. It is
important not to overlook selenium deficiency in
cases of reduced erythropoiesis [54].
HEMATOLOGY 9
Reduced erythropoiesis
Anemia due to hematopoietic stem cell
abnormalities
MDS refers to a cluster of clonal diseases characterized
by morphological dysplasia of hematopoietic stem
cells, hematopoietic failure, and peripheral cell loss,
leading to decreased erythropoiesis. MDS cells,
usually derived from pluripotent hematopoietic stem
cells, are malignant tumors that typically cannot be
cured except through allogeneic stem cell transplan-
tation (SCT) [55]. About 50% of MDS patients possess
somatic mutations in the spliceosome gene, with
SF3B1 being the most frequent one [56], and SF3B1
mutations primarily linked to abnormal 3′ mRNA spli-
cing. In vitro and in vivo, SF3B1K700E cells showed
raised sensitivity to the spliceosome regulator E7107,
and the usage of spliceosome regulators may prove
effective in treating SF3B1 mutational hematologic
malignancies [57]. Moreover, loss or mutations in MDS
and TET2(4q24) have been linked, and TET2 mutations
can cause various disorders such as myeloproliferative
neoplasms, chronic myelomonocytic leukemia, acute
myeloid leukemia, and decreased erythropoiesis [58].
Aplastic anemia (AA) is characterized by marrow
failure (BMF) status, which results in cytopenia and
ineffective hematopoiesis. The disease is classified as
hereditary or acquired, with the latter usually associ-
ated with established germline mutations, and occurs
in two peaks, one in patients aged 15–25 years and
another in those older than 60 years. The prognosis
of severe or very severe acquired AA with supportive
therapy alone is poor, with mortality rates exceeding
80% after two years [59]. The major factors that lead
to AA are direct bone marrow injury, genetic mutations
that reduce the DNA repair capacity of hematopoietic
stem cells, immune factors, and possibly environ-
mental contamination and viral infections [60]. Hema-
topoietic stem cell transplantation is the curative
treatment for AA, while immunosuppressive treatment
(IST) with horse anti thymocyte globulin and cyclos-
porine A is the first-line treatment for elderly patients
and all patients lacking matched sibling donors [61].
Anemia due to abnormal hematopoietic
regulation
Chronic disease anemia (ACD), also acknowledged as
inflammatory anemia (AI), is the second most
common type of anemia worldwide. This type of
anemia is primarily induced by hepcidin, an inflamma-
tory cytokine that regulates iron homeostasis by block-
ing intestinal iron absorption, trapping iron in
reticuloendothelial cells, and reducing iron availability
for erythropoiesis [62]. The transferring of iron from
macrophages to developing erythroid cells also
10 P. TANG AND H. WANG
requires transferrin FPN. In the absence of FPN, iron
remains trapped in macrophages, leading to impaired
iron transferring and erythroid maturation arrest in
developing erythroid cells. Inflammatory cytokines
also decrease EPO synthesis, impair erythroid progeni-
tor differentiation, and shorten the lifespan of mature
erythroid cells [63]. These signals also increase periph-
eral red cell depletion [50].
Oncogenic anemia is a type of chronic disease
anemia associated with the activation of cytokines
like interferon-gamma, interleukin-1, and tumor necro-
sis factor (TNF), which can suppress the output of
endogenous EPO, damage iron utilization, and
decrease erythroid precursor proliferation [64]. Apop-
tosis is a significant contributor to the pathogenesis
of anemia in chronic kidney disease, and approxi-
mately half of the patients with chronic heart failure
anemia also have evidence of endogenous apoptosis
and/or functional iron deficiency [65].
A new treatment for anemia in chronic kidney
disease is the hypoxia-inducible factor proline
hydroxylase inhibitor, which blocks the degradation
of the transcription factor hypoxia-inducible factor, sti-
mulating erythropoiesis to physiological levels [66].
Anemia with abnormal erythrocyte morphology
Erythrocyte abnormalities can manifest as large, small,
or misshapen cells. Normal erythrocytes have a diam-
eter of 7–8 μm and a mean cell volume (MCV) of 80–
95 fl, with larger erythrocytes above this range and
smaller erythrocytes below. The different subgroups
of erythrocyte abnormalities include globin chain
defects (such as hemoglobinemia or thalassemia),
heme synthesis defects, iron availability defects, or pre-
cursor iron acquisition defects [67]. Macrocytic anemia,
which is characterized by enlarged erythrocytes, can
be further categorized into megaloblastic anemia
(caused by defects in RNA and DNA synthesis) and
non-megaloblastic anemia [68].
Plasmodium infection not only reduces erythropoi-
esis but also inhibits the bone marrow’s response to
EPO and leads to abnormalities in nuclear ultrastruc-
ture, including polynuclei, nuclear fragments, internuc-
lear bridges, and irregular nuclear shapes.
Furthermore, parasites have immune escape mechan-
isms that modify host immune responses by increasing
cytokine output, including interleukin-6 (IL-6), IL-12, IL-
1, IL-10, tumor necrosis factor-alpha (TNFalpha), and
interferon-gamma (IFN-gamma). These inflammatory
cytokines can strongly impact erythropoiesis [69].
Thalassemia
Mutations in the hemoglobin synthesis gene lead to
reduced or absent production of α or β-globin chains
and an imbalance in the ratio of α / non-α-globin
chains, resulting in thalassemia.
In beta-thalassemia, mutations in the HBB gene lead
to insufficient production of beta-globin. This leads to
excessive amounts of unstable alpha-globin chains
that aggregate in red blood cell precursors, leading
to ineffective production of red blood cells and prema-
ture destruction of red blood cells [70].
There are two alpha-globin genes on chromosome
16 – α1 and α2, and alpha-thalassemia can be caused
by a deletion or point mutation of one or both alpha-
globin genes, resulting in a defect in the alpha-globin
chain. When alpha-globin production is impaired, excess
β-globin chains form tetramers (HbH) with high oxygen
affinity and poor stability, leading to hemolysis [71].
The severity of thalassemia is determined by the
degree of imbalance in the alpha – / non-alpha
globin ratio. Patients with transfusion-dependent tha-
lassemia (TDT) have severe imbalances and require life-
long transfusions. Patients with non-transfusion-
dependent thalassemia (NTDT) have less imbalance
and anemia.
The body tries to compensate for anemia by
increasing red blood cell production in the bone
marrow. However, this enlarged but ineffective eryth-
rocyte production leads to further abnormalities. For
example, it increases the intestinal absorption of iron
and inhibits the iron-regulating hormone hepcidin.
This can lead to an iron overload in the liver and
heart. Ineffective erythropoiesis also causes bone
marrow dilatation and extramedullary hematopoiesis,
leading to bone abnormalities and splenomegaly [72].
Erythrocytosis
Polycythemia is a condition where the erythrocyte
count exceeds the normal sex range, and it can be
categorized into relative polycythemia induced by a
decrease in plasma volume and absolute polycythemia
induced by an increase in the quality of red blood cells.
Primary polycythemia occurs due to the spontaneous
output of erythrocytes, usually from myeloproliferative
neoplasms (also known as pseudo polycythemia or
PV). On the other hand, secondary polycythemia
occurs when the body responds appropriately to elev-
ated serum erythropoietin levels [73], such as in post-
renal transplant polycythemia where erythropoiesis is
driven by both allografts and native kidneys [74]. Poly-
cythemia includes various types such as thrombosis,
idiopathic polycythemia, congenital polycythemia,
hypoxic lung disease, and post-transplant polycythe-
mia [75]. The majority of polycythemia vera cases are
linked to acquired JAK2 variants. Different types of
familial polycythemia are associated with various
defects, such as erythropoietin hypersensitivity,
defects in the oxygen sensitivity pathway, or an
increase in hemoglobin affinity for oxygen [76]. Poly-
cythemia vera may also result from mutations in the
congenital hypoxia-inducible factor pathway [77]. It is
 HEMATOLOGY 11

Figure 5. Classification of Common Abnormal Erythropoietic Diseases. Abnormalities of erythropoiesis may be classified as
increased erythropoiesis. Reduced erythropoiesis and abnormal erythrocyte morphology. Reduced erythropoiesis can be
divided into hematopoietic stem cell abnormalities, dysregulation of hematopoiesis, and obstruction of hematopoietic material
utilization. Hypererythropoiesis may be classified as primary or secondary, or as relative or absolute, depending on the
amount of red blood cell mass.

crucial to distinguish PV from polycythemia due to
other causes because early detection and treatment
of PV can prevent numerous vasomotor and thrombo-
tic complications. Patients with PV often have an
enlarged plasma volume that can mask the polycythe-
mia, making diagnosis difficult if this basic fact is
ignored [78]. Polycythemia may not cause any symp-
toms, or it may present with thrombosis, vasomotor
symptoms, or splenomegaly [73].
When erythropoiesis is reduced, the body compen-
sates by inducing extramedullary erythropoiesis, also
known as stress erythropoiesis. Unlike the continuous
output of erythrocytes in steady-state erythropoiesis,
stress-induced erythropoiesis produces a large number
of new erythrocytes through synchronous differentiation
of progenitor cells. The bone marrow temporarily
migrates hematopoietic cells to the spleen to re-establish
this process [50]. Early progenitor cells, which are usually
in the quiescent phase, are favored by the HSPC com-
ponent in extramedullary tissue, but proliferation is inhib-
ited [79]. Additionally, anemia stress increases
erythrocyte phagocytosis, and splenic macrophages
promote CCL2 output, which recruits circulating mono-
cytes and forms new hematopoietic islands in the
spleen. Macrophages regulate the circulation of splenic
erythroid cells by removing aging and impaired red
blood cells, and by interacting with developing proto-
red blood cells [80]. Moreover, macrophages interact
with erythroblasts through direct adhesion and indirect
cells, such as erythrocyte-release positive regulators
that inhibit the interaction of specific protein 6 (Gas6),
vascular endothelial growth factor A (VEGF-A), and pla-
cental growth factor (PlGF) to regulate stress erythropoi-
esis [81] (Figure 5).
Therapeutic significance
Anemia has a complex multi-factorial etiology. The main
causes include nutritional deficiencies (iron, vitamin A,
B12, folate), infectious diseases (malaria, HIV, hookworm),
inherited hemoglobin disorders (sickle cell, thalassemia),
and inflammation. Fetal hemoglobin (HbF) induction
remains a promising approach for the treatment of
sickle cell disease and beta-thalassemia. Strategies
include targeting transcription factors that regulate
fetal to adult hemoglobin conversions, such as BCL11A,
KLF1, and MYB, or using epigenetic regulators such as
HDAC and LSD1 inhibitors. Gene therapy using lentiviral
vectors to express the β-globin gene or shRNA targeting
BCL11A in hematopoietic stem cells has shown the
12 P. TANG AND H. WANG
potential to permanently correct hemoglobinopathy.
Gene editing using CRISPR/Cas9 to correct potential
mutations is also being explored. Erythropoietic drugs
such as PHD inhibitors and activin receptor traps (such
as Sotercept) are emerging to treat inflammatory
anemia, chronic kidney disease, cancer, and more. Man-
agement of iron homeostasis with hepcidin modulators,
small hepcidin, or TMPRSS6 inhibitors may help treat iron
overload in patients with transfusion-dependent thalas-
semia. Anti-inflammatory therapies such as selectin
inhibitors, anti-CXCR2, or iNKT cell blocking may alleviate
vaso-blocking crises and organ damage in sickle cell
disease. Enzyme or molecular replacement gene
therapy appears to hold promise for treating rare inher-
ited anemia such as pyruvate kinase deficiency and con-
genital erythropoietic porphyria [53].
For polycythemia vera, maintaining hematocrit
targets of <45% in men and <42% in women by phle-
botomy is the basis of treatment to prevent thrombo-
sis, which is a major immediate health threat. Targeted
therapies such as ruxolitinib and pegylated interferon
can be used for symptom control and to reduce sple-
nomegaly, but their role in preventing thrombosis is
unclear. Hydroxyurea is effective in reducing cells,
but does not affect disease progression, with risks
such as myelofibrosis and leukemia transformation.
Therefore, its use should be limited. Treatment for
pregnant patients includes strict blood pressure
control and phlebotomy, but aspirin and anticoagu-
lants are avoided unless at high risk. Pegylated inter-
feron is safe when necessary. For advanced
myelofibrosis, ruxolitinib, thalidomide-prednisone,
and azacytidine may be selected, but hematopoietic
stem cell transplantation is curable when feasible [78].
In conclusion, erythropoiesis is a complex and
dynamic process that occurs primarily in the marrow,
but can also occur extramedullary under stress con-
ditions. The process is influenced by various factors
including bone marrow microenvironment, macro-
phages, exogenous and endogenous factors, and
intrinsic transcriptional regulators such as GATA and
KLF. Abnormalities in erythropoiesis can lead to
various hematologic disorders such as anemia, erythro-
cytosis, and polycythemia vera. Studies on erythropoi-
esis have provided valuable clinical insights, leading to
the development of new treatments for hematologic
malignancies and anemia, and early recognition and
prevention of thrombosis in polycythemia vera.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The work is funded by National Natural Science Foundation
of China (81170472), the Key Technology Research and
Development Program of Tianjin China (18ZXDBSY00140).
ORCID
Huaquan Wang http://orcid.org/0000-0003-2402-2717
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