Regulation of Erythropoiesis: Emerging Concepts and Implications (2023) PDF

Hematology ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/yhem20 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 To link to this article: https://doi.org/10.1080/16078454.2023.2250645 © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group Published online: 28 Aug 2023. Submit your article to this journal Article views: 6060 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=yhem20 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. Blood islands, which contain primitive erythroid progenitor cells, Erythropoiesis is a process by which red blood cells form in the mesoderm layer of the yolk sac. These pro- (erythrocytes) are produced in the marrow. It involves genitor cells diﬀerentiate into erythroblasts, which the diﬀerentiation of erythroid progenitor cells into produce embryonic hemoglobin (α2ε2). α2ε2 is mature RBCs, which transport oxygen from the lungs composed of a pair of alpha and a pair of epsilon to the body’s tissues. erythropoiesis is a complex globin chains and has a stronger aﬃnity for oxygen process that is strictly regulated by varieties of than adult hemoglobin. factors, including hormones, cytokines, and growth Around 6–8 weeks of gestation, erythropoiesis shifts factors. to the hepar and spleen , as these organs become In recent years, there have been vital advances in capable of producing erythropoietin (EPO), the our awareness of the molecular mechanisms that hormone that stimulates erythropoiesis. Studies show govern erythropoiesis. These advances have led to that EMP produced in the mouse yolk sac migrates the positive result of new therapeutic strategies for to the hepar and colonizes , and hematopoietic the treatment of erythropoietic disorders. In the stem cells also migrate to the hepar. The hepar article, we review the issues of embryonic erythropoi- becomes the primary site of erythropoiesis from esis, the cytokines involved in erythropoiesis, signaling around weeks 10–28 of gestation, while the spleen cascades, and possible problems in erythropoiesis. mainly produces RBCs in the second trimester. By the end of the second trimester, erythropoiesis The normal physiological course of begins to shift to the marrow, which becomes the erythropoiesis initial site of erythropoiesis by the time of birth (Figure 1). At this stage, fetal hemoglobin (HbF) is the Erythropoiesis in embryos primary type of hemoglobin produced, which pos- In embryos, erythropoiesis occurs in a diﬀerent sesses a stronger aﬃnity for oxygen than adult hemo- location than in adults. During embryonic develop- globin (HbA) and helps to facilitate oxygen transport ment, erythropoiesis initially takes place in the yolk across the placenta. After birth, the output of HbF sac, and later shifts to the hepar and spleen, before gradually decreases and is replaced by the output of ultimately transitioning to the marrow. HbA. The Yolk sac is the original site of erythropoiesis Fetal hematopoiesis is regulated by multiple factors. during the ﬁrst few weeks of embryonic development For example, ferritin IRP2 regulates iron infusion from , and it’s a short-lived membrane which is gradually the maternal placenta , and EpoR can lengthen the CONTACT Huaquan Wang [email protected] © 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 In the bone marrow, erythroid progenitor cells cell cycle length. Furthermore, growth factors (SCF) diﬀerentiate into erythroblasts, which undergo are critical for erythropoiesis and are critical for main- several rounds of cell division and synthesis of hemo- taining normal adult erythrocyte numbers. globin, the protein that brings oxygen in RBCs. The Erythropoiesis ﬁrst occurs in the yolk sac, then metas- cells gradually reduce their size and nucleus, and tasizes to the fetal liver, and ﬁnally resides in the bone increase their cytoplasmic volume, ultimately becom- marrow after birth. Switching between these sites is ing reticulocytes. associated with changes in globin expression and The output of erythroblasts is regulated by a oxygen-binding aﬃnity of erythrocytes. When erythro- number of cytokines and growth factors, including ery- cyte proliferation metastasizes from the yolk sac to the thropoietin (EPO), stem cell factor (SCF), and interleu- fetal liver, a primordial to ﬁnal erythroblastic transform- kin-3 (IL-3), among others. EPO, which is produced ation occurs. Fetal to adult globin conversion occurs primarily by the kidneys in response to low oxygen when erythropoiesis is transferred from the fetal liver levels in the body, excites the diﬀerentiation and pro- to the bone marrow. Fetal globin has a higher oxygen liferation of erythroid progenitor cells. aﬃnity than adult globin and can better extract The process of erythropoiesis in the bone marrow is oxygen from maternal blood. These spatial and tem- also aﬀected by the microenvironment, or niche, in poral switches during erythropoiesis allow the develop- which the cells remain. This niche consists of various ing embryo/fetus to adapt to the changing oxygen cell types, containing osteoblasts, endothelial cells, requirements during development. stromal cells, as well as extracellular matrix com- ponents. Osteoblasts, which are bone-forming cells, have Erythropoiesis in bone marrow been shown to regulate erythropoiesis through the Erythropoiesis in bone marrow is the process by which output of cytokines and growth factors, as well as progenitor cells become mature red blood cells (RBCs), direct cell-to-cell contacts with erythroid progenitor about 20 billion erythrocytes emerge in the marrow cells. Endothelial cells also play a role in regulating ery- every day. This course is regulated and controlled thropoiesis by producing cytokines and growth by a heterogeneous network of signaling pathways factors, and by providing a source of oxygen and and transcription factors. other nutrients. Stromal cells, which are mesenchymal HEMATOLOGY 3 cells that support hematopoiesis, also contribute to impaired erythropoiesis and anemia. Stress erythropoi- the regulation of erythropoiesis by producing growth esis is highly dependent on signals such as EPO/EPOR/ factors and providing a supportive niche for erythroid JAK2/STAT5, as well as activation signals in erythroid progenitor cells (Figure 2). islets such as BMP4/SMAD5 and integrin signals. Terminal enucleation is the process by which the nucleus is extruded from late erythrocytes before Stages of RBC maturation and diﬀerentiation they mature into reticular cells. This is a unique feature of mammalian erythrocyte production. Erythropoiesis is a multi-stage process that typically Some congenital dysplasia of erythropoietic anemia lasts for approximately 14 days. It includes the (CDAs) and myelodysplastic syndrome (MDS) may diﬀerentiation of hematopoietic stem cells into ery- have a pathological phenomenon of erythrocyte enu- throid progenitor cells and megakaryocytes. Ery- cleation disorder. In MDS, abnormal erythrocyte throid progenitor cells consist of erythroid bursting islands and poor erythrocyte segregation may indi- forming units (BFU-E) and erythroid colony forming cate impaired peripheral enucleation. In CDA type I, units (CFU-E), which are a continuous stage of ery- caused by CDAN1 or C15orf41 mutations, the throid progenitor cells. These cells then diﬀer- encoded proteins are thought to have roles in chro- entiate into erythroid precursors of varying matin remodeling during nuclear extrusion. In CDA morphologies. type II caused by SEC23B mutations, SEC23B may The earliest recognizable erythroid precursor cells be involved in mesomeric formation during cell div- are pro-erythroblasts (pro-E), which mark the begin- ision, and its dysfunction can lead to impaired enu- ning of the second stage of red blood cell (RBC) matu- cleation. In CDA type III, caused by a KIF23 ration. Pro-E cells develop into basophilic (Bas-E), mutation, the mutant protein disrupts cytokinesis polychromatic (Poly-E), and orthochromatic erythro- through eﬀects on the mitotic spindle apparatus. In cytes (Ortho-E) in a sequential manner, ultimately these cases, the molecular mechanisms of impaired leading to the formation of reticulocytes that lack a enucleation are not fully understood, but may nucleus. During this process, the size of the cells involve protein dysfunction involved in the regu- and nuclei gradually decreases while the accumulation lation of chromatin remodeling, cell division, and of hemoglobin increases. erythrocyte island formation. Late-stage erythropoiesis is characterized by the loss of the nucleus, loss of surface biomarkers, and the formation of a strong and extendable cytoskeleton. Erythroblast island These changes allow for the ﬁnal maturation and Erythroblast island refers to a unique microenviron- diﬀerentiation of erythroid precursors to fully mature ment in the marrow where erythroblasts, the precur- erythrocytes. sors of erythrocytes, interact with macrophages. The erythroblast island is symbolized by a central macro- Biomarkers of erythropoiesis phage surrounded by a circle of developing erythroblasts. Studies utilizing single-cell genomics have demon- Macrophages within the erythroblast island play an strated that the output of erythrocytes (RBCs) is an important role in supporting erythropoiesis, the course ongoing process characterized by varying cellular by which progenitor cells diﬀerentiate into mature states and the expression of diﬀerent genes. erythrocytes. Macrophages provide various factors The progenitor cells, BFU-E and CFU-E, are highly such as transferrin, iron, cytokines, and growth enriched in the umbilical cord and bone marrow factors to support erythropoiesis. as well as peripheral blood, as indicated by the The erythroblasts in the erythroblast island depend expression of CD34, CD105, CD36, CD71, and on the macrophages for survival and diﬀerentiation. CD45RA markers. By using CD34/CD105 and GPA/ Macrophages provide adhesion molecules and phago- CD105 spectra, all four progenitor stages and ﬁve cytose the extruded nuclei and organelles from eryth- terminal erythroid diﬀerentiation stages can be roblasts. Additionally, macrophages produce growth identiﬁed. factors and cytokines like erythropoietin, stem cell Further diﬀerentiation of human erythroid precur- factor, and insulin-like growth factor-1, which sors can be classiﬁed by surface expression of the promote erythropoiesis and the proliferation of transferrin receptor (CD71) and glycoprotein A erythroblasts. (CD235a). Additionally, the expression of Integrin The close association between macrophages and α4 (CD49D) and band three protein has been erythroblasts within the erythroblast island creates a found to promote the resolution of multifarious supportive microenvironment that stimulates the stages of erythroid precursor diﬀerentiation. A eﬃcient output of functional erythrocytes. Dysfunction combination of GYPA (CD235A) and CD105 or disruption of this microenvironment can lead to 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 maturation. In mice, Ter119, CD71, and HE4 erythroid maturation. are markers of progenitor cells and erythrocytes, Biomarkers of erythropoiesis in human and mouse and Ter119 is a marker of mature red blood cells. is totally diﬀerent. In humans, miR-451 and miR-144 In addition to EPO, SCF and IL-3 are key cytokines are highly expressed during erythropoiesis and play that regulate early erythrocyte production in mice. an important role in promoting erythrocyte diﬀeren- Similar to humans, TGF-β signaling also negatively tiation. They are located in the same gene cluster regulates late erythropoiesis in mice. Transcription and are regulated by the red transcription factor factors such as GATA-1 and KLF1 are key mouse ery- GATA1. miR-486 is also upregulated during erythropoi- throid regulators. esis and collaborates with GATA1 as a regulator of erythrocyte diﬀerentiation. miR-221 and miR-222 are down-regulated during the diﬀerentiation of human Regulatory mechanisms of erythropoiesis hematopoietic progenitor cells into red blood cells. Exogenous regulation and control of miR-320 is associated with the expression of CD71 erythropoiesis protein, a marker of reticular cell maturation in human sickle cell anemia. CD71 and CD36 in early pro- Varieties of external elements can activate essential genitor cells, glycoprotein A in late progenitor cells/ downstream signaling pathways that regulate the precursors, and CD235a in mature red blood cells are diﬀerentiation, proliferation, and survival of erythro- key markers of human erythropoiesis. cytes. One such factor is IL-3, which can stimulate the In mice, as in humans, miR-451 and miR-144 are proliferation of early progenitors, containing BFU-E. key red blood cell biomarkers in mice that promote Additionally, KIT ligands can bind to KIT (CD117), pro- erythropoiesis when overexpressed. miR-150 is moting the proliferation of BFU-E, CFU-E, and erythro- down-regulated during erythrocyte terminal diﬀeren- blasts. tiation in mice. miR-221, miR-222 and miR-223 were Wnt signaling also plays a part in the regulation of down-regulated during erythropoiesis in mice. let-7 erythropoiesis, particularly in the terminal diﬀeren- miRNA is upregulated during mouse erythrocyte tiation of erythrocytes in myeloid sinusoidal HEMATOLOGY 5 endothelial cells, as well as in the maturity of reticulo- 1000-fold in response to tissue hypoxia. In mice, cytes and the overall function of red blood cells and HIF2a speciﬁcally activates EPO, which is required for hematopoietic cells in mesenchymal stromal cell popu- EPO expression in the kidney and hepar. Destruction lations. 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 Regulation of erythropoiesis by EPO by EPO-derived factors. Osteoblasts can also gen- erate EPO to promote erythropoiesis under stable con- EPO is a glycoprotein that plays a crucial role in adjust- ditions of constitutive HIF. Exogenous EPO and the ing erythrocyte quality and hematopoiesis in transloca- formation of bone have a connection with raised tion and formation of erythrocyte transcriptional bone marrow vascular density and angiogenesis in programs. During stress erythropoiesis, EPO many repair models. EPO directly stimulates osteogen- quickly improves the appearance of the anti-apoptotic esis by targeting mesenchymal stromal cells and regulator BCL-XL in early erythrocytes by STAT5 and hematopoietic stem cells, and indirectly stimulates inhibits the pro-apoptotic proteins BIMsponse to alter- osteoblast diﬀerentiation by irritating HSCs to secrete nations in tissue oxygenation. EPO is produced by bone morphogenetic proteins. EPO also directly stimu- renal stromal cells in adults and mainly by the hepar in lates osteoblast diﬀerentiation toward mature osteo- embryos. EPO contributes to hematopoiesis of hema- clasts via Jak2 and PI3K pathways, resulting in an topoietic stem and progenitor cells (HSPC) by promot- according decline in EPOR transcript levels ing erythroid proliferation and survival from CFU-E, (Figure 3). which rapidly decreases with the terminal maturation of the cell. Regulation of erythropoiesis and iron EPO induces erythropoiesis by binding to EPO metabolism by the ERFE-ferritin-transferritin receptor (EPOR) on precursors of erythroid cells in axis the marrow, promoting their survival, proliferation, and diﬀerentiation. EPOR is expressed primarily on The regulation of iron metabolism and erythropoiesis CFU-E, erythrocytes, and early basophils. Binding to is crucial, and it also involves the ERFE-ferritin-trans- EPO prevents apoptosis of these erythroid progenitors ferrin axis. Approximately two-thirds of the. body’s iron is stored in RBCs. RBCs require 20– The EPO/EPOR pathway stimulates erythroid devel- 25 mg of iron daily, which is supplied by iron trans- opment by activating the JAK2/STAT3/STAT5 pathway, port proteins that contain only 3 milligrams of iron at which aids in Nucl, NOXA, Fas, and FasL. EPO also any given moment and are replaced every several stimulates erythroid precursor cells in the marrow and hours. Since the human body cannot excrete spleen to quickly produce erythroferrone (ERFE) by iron, the balance between iron intake, transport, util- STAT5. ization, and storage must be tightly regulated. Activation of STAT3 by EPO/EPO receptors leads to Iron required by RBCs is obtained largely from increased expression of genes involved in red blood macrophages phagocytosing old RBCs, and is sup- cell progenitor cell survival (Bcl-xL), proliferation, and plied daily by 20–25 mg of iron, which is absorbed diﬀerentiation. A key target of STAT3 is the transcrip- in the intestine by 1–2 mg (0.05% of total iron tion factor GATA-1, which regulates the expression of content in the body) to make up the iron loss due many red blood-cell speciﬁc genes, including those to intestinal epithelial cell loss and a small amount involved in hemoglobin production. STAT3 is rigidly of blood loss in the skin. and brieﬂy regulated during erythropoiesis through Non-heme iron can be absorbed from the lumen by EPO-mediated JAK2 activation, followed by rapid feed- the divalent metal transport protein 1 (DMT1) located back inhibition through SOCS protein, phosphatase, at the apical surface of epithelial cells in the duodenum and proteasome degradation to prevent overactivity. by the duodenal cytochrome B reductase (DCYTB), This allows STAT3 to induce erythroid gene expression which reduces iron to ferrous metal, and heme iron in a precise manner to match the physiological require- is absorbed more eﬃciently in the gut than non- ments of red blood cell production. heme iron. Absorbed iron can be utilized by intes- JAK2 inactivation leads to anemia, whereas JAK2 tinal cells, kept in ferritin, or transported to the circula- mutations lead to raised erythrocyte quantity and ery- tion by iron a basolateral membrane of the intestinal throcytosis. EPO and EPOR play critical roles in erythro- cells. Iron absorption and tissue distribution are cyte quality control, and their dysregulation can result regulated mainly by the interaction of the hepar hor- in various hematological disorders. mones hepcidin and ferritin. Ferritin exerts its function During hypoxia, the highly conserved hypoxia-indu- through three common forms: ferritin coordinated by cible factor (HIF) signaling pathway is activated, and the side chains of proteins, ferritin in the heme loop, the ﬁrst target of HIF is EPO. EPO levels increase by 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 similar to general ligand-induced endocytosis in vivo. and their precursors in erythropoiesis-producing This process is triggered by transporter conformational organs), two storage locations (hepatocytes in the changes induced by ferritin, leading to ubiquitin of the hepar, macrophages in the spleen and hepar), lysine-rich cytoplasmic fraction that links the two six- plasma transporting iron between tissues and organs, helix regions of ferritin. Ferritin is then targeted for and absorptive intestinal cells in the duodenum. lysosomal and proteasomal degradation through ubi- Erythroferrone (ERFE) is a protein synthesized and quitination, which is facilitated by Rnf217, an impor- secreted by red blood cells in the marrow and tant E3 ubiquitin ligase [26,34]. extramedullary regions, and is induced by EPO Hepcidin is regulated by various factors including output. ERFE belongs to the C1Q tumor necrosis plasma iron concentration (majorly relying on the factor-related protein family, and acts directly in contact of ferritin with the transferrin receptors TFR1 the hepar to decrease hepcidin expression. Unlike and TFR2), hepar iron reserve, systemic inﬂammation EPO, which can stimulate erythropoiesis in both signals transmitted majorly by IL-6 to hepatocytes, stress and homeostatic conditions, ERFE only and erythroid activity signals transmitted mainly responds to stress erythropoiesis. ERFE inhibits hep- through ERFE concentration. Excessive iron can cidin expression, increases the supply of iron, and be toxic and cause oxidative DNA damage , and helps maintain iron balance during periods of high in patients with iron overload, hepcidin levels are elev- erythropoietic demand. ated. The combination of hepcidin and ferritin results Ferritin is synthesized in the hepar and upon in the rapid degradation of hepcidin. When systemic binding to iron, it undergoes ubiquitination and gets iron levels are low, this results in decreased expression degraded in the lysosomes. This process reduces the of hepcidin and raised iron mobilization. Hypoxia inhi- transfer of ferritin to the cell membrane, keeps iron bits hepcidin expression, and the hypoxia-induced inside the cell, and lowers the amount of iron in the hepcidin inhibition, unrelated to EPO and erythrocyte blood. The regulation of ferritin by endocytosis is output, is mediated by hypoxia-mediated degradation HEMATOLOGY 7 of C/EBPA, a key transcription factor required for hep- addition to hepcidin, inﬂammatory stimulation in the cidin basal expression. Hepar hypoxia is a strong form of Toll-like receptor ligands straightly inhibits cel- inhibitor of hepcidin expression during hepar inﬂam- lular ferritin mRNA quantity and reduces cellular mation and IL-6 output. HIF has a hand in the suppres- plasma iron output. sion of hepcidin, and animal studies have shown that The transferrin (Tf) complex binds one iron mol- HIF activation in the mouse hepar decreases hepcidin ecule and has two receptors, TFR1 and TFR2. TFR1 expression and increases ferritin in the intestine and mediates the internalization of Tf in the iron-transfer macrophages. Stressful and ineﬀective erythropoi- pathway, and it can bind partially saturated transferri- esis can also inhibit ferritin. GDF15 and TWSG1, tin, as well as iron in both the light and heavy chains of members of the transforming growth factor B super- ferritin. The aﬃnity of TFR1 for c-valve and n-valve family, are considered to be pathological inhibitors of saturated transferritin is only 5 and 6 times that of hepcidin in ineﬀective erythropoiesis., GDF15 and Apo-Tf, respectively. At physiological pH levels, Tf is TWSG1 inhibit hepcidin expression (Figure 4). discharged from TFR1 to the serum, where it can HIF2α is activated in the intestine when there are combine with iron again. The IRE/IRP system low levels of iron in the epithelium, leading to an increases TFR1 expression. The IRE/IRP system func- increase in hepcidin-mediated degradation of ferritin. tions to regulate cellular iron homeostasis, ensuring During iron deﬁciency, PHD activity is reduced, which that cells can increase TfR1 expression when the iron further enhances the expression of HIF2α. Although supply is insuﬃcient, thereby enhancing iron absorp- intestinal iron levels do not change during erythropoi- tion and utilization eﬃciency. Once the cellular iron esis, the decreased oxygen levels in the intestine result level reaches an appropriate level, IRP dissociates in HIF2α activation. Hepcidin exhibits bacteriostatic from the IRE, leading to a decrease in TfR1 expression eﬀects on several bacteria and fungi. to prevent excessive iron uptake. When the cellular The transferrin (Tf) complex consists of two lobes, iron level is low, IRP binds to the IRE (iron-responsive each of which can bind one iron atom. The degree of element) located in the 3′ UTR (untranslated region) Tf saturation reports the body’s iron capacity, which of TfR1 mRNA, stabilizing its structure and promoting is typically between 20% and 45% in healthy human the stability and translation of TfR1 mRNA. As a beings. Transferrin is the only iron transport result, the expression level of TfR1 increases, allowing protein known so far. Stable transferrin binding to cells to more eﬀectively uptake iron. TFR1 is over- the cell membrane stimulates iron absorption by the expressed in diﬀerentiated erythroid cells. Nuclear duodenum, enhances iron recovery by macrophages endosomes including Holo-Tf-TFR1 approach the mito- from old red blood cells and other cells, and allows chondria and transfer iron to the organelle by rapid the transfer of iron contained in the hepar. Most and transient contact with the mitochondria, restrain- transferrin molecules are bound with hepcidin most ing the cytoplasmic iron pool without triggering the of the time, and this mechanism is quickly adjustable adjustment of the IR/IRP system. 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. 8 P. TANG AND H. WANG Tfr2 is a transmembrane glycoprotein that acts as a (NURD) complexes, promote the binding of GATA1 to receptor for circulating iron. It’s similar to the classical regulatory sites. transferrin receptor Tfr1. Tfr2 plays an important part in During erythroid cell development, GATA factor regulating iron homeostasis by controlling hepcidin switching occurs, whereby GATA2 protein levels are levels. Loss-of-function mutations in Tfr2 result in low decreased and GATA1 protein levels are raised. levels of hepcidin, excess circulating iron, and hemo- GATA1 targets several genes that are regulated by chromatosis , while mutations in hepcidin cause GATA2 in hematopoietic stem and progenitor cells severe hereditary iron overload.. In erythroid cells, GATA1 occupies both the pro- Unlike TFR1, TFR2 is not adjusted by the IR/IRP moter and enhancer, but the enhancer activity system. TFR2 expression is instead regulated post- decreases during diﬀerentiation, with GATA1 predomi- translationally by its ligand, Holo-Tf. TFR2 protects nantly binding to the promoter. Enhancers play a more ferrous plasma Tf from lysosomal degradation and is a signiﬁcant role in the early stages of cell diﬀerentiation, part of the erythroid progenitor EpoR complex, critical while promoters are more critical in the terminal for valid transfer of EpoR to the cell surface and ﬁnal stages. diﬀerentiation. In mouse erythroid progenitors, the GATA2 tran- Hepatic TfR2 stimulates iron signaling to ferritin scription factor increases the production of the stem to repress further iron inﬂux into the blood when cell cytokine receptor KIT, while GATA1 is responsible iron is present. In contrast, erythroid TfR2 limits for reducing KIT expression to promote terminal diﬀer- Epo sensitivity to prevent overdose erythropoiesis. entiation. However, in human erythroid progenitors, Under iron-deﬁcient conditions, TfR2 becomes high levels of KIT expression require GATA1 binding unstable, leading to hepatic TfR2 downregulation, on erythroid-speciﬁc SE. which inhibits iron signaling to ferritin, stimulates GATA1 is regulated by various factors at the post- cellular iron excretion, and increases iron supply to transcriptional level. HSP27 and HSP70 members of RBC. Reduction of erythroid TfR2 promotes Epo’s the heat shock protein family, along with ribosomal sensitivity to erythropoiesis and contributes to the proteins, promote the ubiquitination and proteaso- suppression of hepcidin by ERFE. mal degradation of GATA1. HSP70 also plays a role in preventing the caspase-3-mediated intranuclear division of GATA1, while ribosomal proteins regulate Transcriptional control of erythropoiesis the normal translation of GATA1. Additionally, RBC output is regulated by intrinsic transcription there is an interaction between GATA1 and p53, factors that regulate the diﬀerentiation of erythroid which inhibits RNA Pol I transcription by restricting cells. Among these transcription factors, GATA1 plays the RNA Pol I complex from assembling on the an important part in directing the diﬀerentiation of rDNA facilitator. In cancer, the loss of function of erythroid cells towards RBC lineage. Another key tran- p53 and mass output of ribosomes may lead to scription factor involved in RBC output is KLF1. the inhibition of GATA1 by p53. On the other Mutations in GATA1 and KLF1 are associated with hand, downregulation of p19INK4d reduces GATA1 various types of anemia in humans. These transcrip- protein levels and impairs human terminal erythroid tion factors activate and suppress regulatory networks diﬀerentiation, which is adjusted by the p-ERK- involved in RBC output and have diﬀerent functions in HSP70-GATA1 pathway, where PEBP1 serves as a this process. connection between p19INK4d and the p-ERK- HSP70-GATA1 pathway. Transcriptional regulation of GATA in erythropoiesis Transcriptional regulation of KLF1 in erythropoiesis The GATA transcription factor, which contains zinc- ﬁnger DNA binding domains, is critical for various bio- KLF1 is a protein that is abundant in erythroid cells and logical processes, including hematopoiesis. GATA contains three C2H2 zinc ﬁngers at its C-terminus. It factors interact with speciﬁc regulatory elements to connects its DNA consensus sequence (5′ ccmcrcccn) mediate transcriptional changes. GATA-1 is essen- mainly in the distal regulatory region, and is expressed tial for the existence and diﬀerentiation of progenitors in both primitive and nucleated erythrocytes within of red blood cells, while GATA-2 adjusts the survival the hematopoietic compartment. Its primary role and proliferation of hematopoietic stem and progeni- in erythropoiesis is the activation of gene transcription, tor cells. GATA1 has three functional domains, and it inhibits the diﬀerentiation of megakaryocytes including an N-terminal activation domain and two while promoting early diﬀerentiation of RBCs. homologous Zn ﬁnger domains located in the C-term- KLF1 plays an important part in the ﬁnal stages of inal region. Various cofactors, such as FOG-1/ the cell cycle and chromatin condensation, which ZFPM1, nuclear remodeling bodies, and deacetylase stimulate RBC output. In the absence of KLF1, RBC HEMATOLOGY 9 denuclearization is impaired, CDKN2C and CDKN1A Reduced erythropoiesis levels are reduced, and RBC proliferation is raised. Anemia due to hematopoietic stem cell Although KLF1 is predominantly a transcriptional acti- abnormalities vator, it can also act as a transcriptional inhibitor. Coactivator-coinhibitory interactions under KLF1 MDS refers to a cluster of clonal diseases characterized acetylation dynamically regulate downstream tran- by morphological dysplasia of hematopoietic stem scriptional eﬀects. cells, hematopoietic failure, and peripheral cell loss, leading to decreased erythropoiesis. MDS cells, usually derived from pluripotent hematopoietic stem Transcriptional regulation of erythropoiesis by cells, are malignant tumors that typically cannot be other factors cured except through allogeneic stem cell transplan- tation (SCT). About 50% of MDS patients possess TGF-beta is a crucial factor in cell diﬀerentiation and somatic mutations in the spliceosome gene, with has signiﬁcant eﬀects on hematopoiesis. TGFβ1 SF3B1 being the most frequent one , and SF3B1 is involved in cell survival, proliferation, and diﬀeren- mutations primarily linked to abnormal 3′ mRNA spli- tiation. Megakaryocytes are the primary source of cing. In vitro and in vivo, SF3B1K700E cells showed TGFβ1 in the bone marrow, but they can also be syn- raised sensitivity to the spliceosome regulator E7107, thesized by immune cells, macrophages, and marrow and the usage of spliceosome regulators may prove stromal cells. TGFβ1 inhibits early progenitor cell pro- eﬀective in treating SF3B1 mutational hematologic liferation and stimulates erythroid terminal diﬀeren- malignancies. Moreover, loss or mutations in MDS tiation through Smad2/3-Smad4 or tiﬀ-1g signaling. and TET2(4q24) have been linked, and TET2 mutations Dysregulation of TGFβ1 may lead to myeloﬁbrosis, can cause various disorders such as myeloproliferative while blocking it may result in the proliferation of ery- neoplasms, chronic myelomonocytic leukemia, acute throid progenitors. Additionally, members of the myeloid leukemia, and decreased erythropoiesis. TGFβ family promote the degradation of HIF1α by inhi- Aplastic anemia (AA) is characterized by marrow biting VHL, an E3 ubiquitin ligase, which enhances failure (BMF) status, which results in cytopenia and hypoxia responses. ineﬀective hematopoiesis. The disease is classiﬁed as hereditary or acquired, with the latter usually associ- ated with established germline mutations, and occurs Unusual and common erythropoietic in two peaks, one in patients aged 15–25 years and disorders another in those older than 60 years. The prognosis Anemia is a condition characterized by a hemoglobin of severe or very severe acquired AA with supportive level below 13 g/dL in adult males and below 12 g/ therapy alone is poor, with mortality rates exceeding dL in non-pregnant females , and can result from 80% after two years. The major factors that lead decreased erythropoiesis, excessive red blood cell to AA are direct bone marrow injury, genetic mutations destruction, or blood loss. Reduced erythropoiesis that reduce the DNA repair capacity of hematopoietic can be sorted into several categories, including anemia stem cells, immune factors, and possibly environ- caused by abnormalities in hematopoietic stem cells mental contamination and viral infections. Hema- (e.g. aplastic anemia, PRCA, myelodysplastic syndrome, topoietic stem cell transplantation is the curative leukemia), abnormalities in hematopoietic regulation treatment for AA, while immunosuppressive treatment (e.g. myeloid necrosis, myeloﬁbrosis, tumor disease, (IST) with horse anti thymocyte globulin and cyclos- myeloid metastasis, bone marrow stromal-cell- porine A is the ﬁrst-line treatment for elderly patients involved diseases), hyperlymphocyte dysfunction (e.g. and all patients lacking matched sibling donors. AA and immune-associated pancytopenia), abnormal- ities in hematopoietic regulatory factors (e.g. chronic disease-associated anemia), hyperapoptosis (e.g. par- Anemia due to abnormal hematopoietic oxysmal nocturnal hemoglobinuria), or deﬁciency of regulation hematopoietic materials (e.g. iron-deﬁciency anemia, deﬁciency of iron, leucine, and vitamin B12, and mega- Chronic disease anemia (ACD), also acknowledged as loblastic anemia). Additionally, low levels of sel- inﬂammatory anemia (AI), is the second most enium, which is involved in redox reactions by common type of anemia worldwide. This type of binding to the selenium family of cysteine-containing anemia is primarily induced by hepcidin, an inﬂamma- proteins and has an antioxidant eﬀect, can lead to tory cytokine that regulates iron homeostasis by block- reduced erythroid cell number and diﬀerentiation ing intestinal iron absorption, trapping iron in under stress, resulting in an ineﬀective response. It is reticuloendothelial cells, and reducing iron availability important not to overlook selenium deﬁciency in for erythropoiesis. The transferring of iron from cases of reduced erythropoiesis. macrophages to developing erythroid cells also 10 P. TANG AND H. WANG requires transferrin FPN. In the absence of FPN, iron In beta-thalassemia, mutations in the HBB gene lead remains trapped in macrophages, leading to impaired to insuﬃcient production of beta-globin. This leads to iron transferring and erythroid maturation arrest in excessive amounts of unstable alpha-globin chains developing erythroid cells. Inﬂammatory cytokines that aggregate in red blood cell precursors, leading also decrease EPO synthesis, impair erythroid progeni- to ineﬀective production of red blood cells and prema- tor diﬀerentiation, and shorten the lifespan of mature ture destruction of red blood cells. erythroid cells. These signals also increase periph- There are two alpha-globin genes on chromosome eral red cell depletion. 16 – α1 and α2, and alpha-thalassemia can be caused Oncogenic anemia is a type of chronic disease by a deletion or point mutation of one or both alpha- anemia associated with the activation of cytokines globin genes, resulting in a defect in the alpha-globin like interferon-gamma, interleukin-1, and tumor necro- chain. When alpha-globin production is impaired, excess sis factor (TNF), which can suppress the output of β-globin chains form tetramers (HbH) with high oxygen endogenous EPO, damage iron utilization, and aﬃnity and poor stability, leading to hemolysis. decrease erythroid precursor proliferation. Apop- The severity of thalassemia is determined by the tosis is a signiﬁcant contributor to the pathogenesis degree of imbalance in the alpha – / non-alpha of anemia in chronic kidney disease, and approxi- globin ratio. Patients with transfusion-dependent tha- mately half of the patients with chronic heart failure lassemia (TDT) have severe imbalances and require life- anemia also have evidence of endogenous apoptosis long transfusions. Patients with non-transfusion- and/or functional iron deﬁciency. dependent thalassemia (NTDT) have less imbalance A new treatment for anemia in chronic kidney and anemia. disease is the hypoxia-inducible factor proline The body tries to compensate for anemia by hydroxylase inhibitor, which blocks the degradation increasing red blood cell production in the bone of the transcription factor hypoxia-inducible factor, sti- marrow. However, this enlarged but ineﬀective eryth- mulating erythropoiesis to physiological levels. rocyte production leads to further abnormalities. For example, it increases the intestinal absorption of iron and inhibits the iron-regulating hormone hepcidin. Anemia with abnormal erythrocyte morphology This can lead to an iron overload in the liver and Erythrocyte abnormalities can manifest as large, small, heart. Ineﬀective erythropoiesis also causes bone or misshapen cells. Normal erythrocytes have a diam- marrow dilatation and extramedullary hematopoiesis, eter of 7–8 μm and a mean cell volume (MCV) of 80– leading to bone abnormalities and splenomegaly. 95 ﬂ, with larger erythrocytes above this range and smaller erythrocytes below. The diﬀerent subgroups Erythrocytosis of erythrocyte abnormalities include globin chain defects (such as hemoglobinemia or thalassemia), Polycythemia is a condition where the erythrocyte heme synthesis defects, iron availability defects, or pre- count exceeds the normal sex range, and it can be cursor iron acquisition defects. Macrocytic anemia, categorized into relative polycythemia induced by a which is characterized by enlarged erythrocytes, can decrease in plasma volume and absolute polycythemia be further categorized into megaloblastic anemia induced by an increase in the quality of red blood cells. (caused by defects in RNA and DNA synthesis) and Primary polycythemia occurs due to the spontaneous non-megaloblastic anemia. output of erythrocytes, usually from myeloproliferative Plasmodium infection not only reduces erythropoi- neoplasms (also known as pseudo polycythemia or esis but also inhibits the bone marrow’s response to PV). On the other hand, secondary polycythemia EPO and leads to abnormalities in nuclear ultrastruc- occurs when the body responds appropriately to elev- ture, including polynuclei, nuclear fragments, internuc- ated serum erythropoietin levels , such as in post- lear bridges, and irregular nuclear shapes. renal transplant polycythemia where erythropoiesis is Furthermore, parasites have immune escape mechan- driven by both allografts and native kidneys. Poly- isms that modify host immune responses by increasing cythemia includes various types such as thrombosis, cytokine output, including interleukin-6 (IL-6), IL-12, IL- idiopathic polycythemia, congenital polycythemia, 1, IL-10, tumor necrosis factor-alpha (TNFalpha), and hypoxic lung disease, and post-transplant polycythe- interferon-gamma (IFN-gamma). These inﬂammatory mia. The majority of polycythemia vera cases are cytokines can strongly impact erythropoiesis. linked to acquired JAK2 variants. Diﬀerent types of familial polycythemia are associated with various Thalassemia defects, such as erythropoietin hypersensitivity, Mutations in the hemoglobin synthesis gene lead to defects in the oxygen sensitivity pathway, or an reduced or absent production of α or β-globin chains increase in hemoglobin aﬃnity for oxygen. Poly- and an imbalance in the ratio of α / non-α-globin cythemia vera may also result from mutations in the chains, resulting in thalassemia. congenital hypoxia-inducible factor pathway. 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 erythroid cells by removing aging and impaired red other causes because early detection and treatment blood cells, and by interacting with developing proto- of PV can prevent numerous vasomotor and thrombo- red blood cells. Moreover, macrophages interact tic complications. Patients with PV often have an with erythroblasts through direct adhesion and indirect enlarged plasma volume that can mask the polycythe- cells, such as erythrocyte-release positive regulators mia, making diagnosis diﬃcult if this basic fact is that inhibit the interaction of speciﬁc protein 6 (Gas6), ignored. Polycythemia may not cause any symp- vascular endothelial growth factor A (VEGF-A), and pla- toms, or it may present with thrombosis, vasomotor cental growth factor (PlGF) to regulate stress erythropoi- symptoms, or splenomegaly. esis (Figure 5). When erythropoiesis is reduced, the body compen- sates by inducing extramedullary erythropoiesis, also known as stress erythropoiesis. Unlike the continuous Therapeutic signiﬁcance output of erythrocytes in steady-state erythropoiesis, Anemia has a complex multi-factorial etiology. The main stress-induced erythropoiesis produces a large number causes include nutritional deﬁciencies (iron, vitamin A, of new erythrocytes through synchronous diﬀerentiation B12, folate), infectious diseases (malaria, HIV, hookworm), of progenitor cells. The bone marrow temporarily inherited hemoglobin disorders (sickle cell, thalassemia), migrates hematopoietic cells to the spleen to re-establish and inﬂammation. Fetal hemoglobin (HbF) induction this process. Early progenitor cells, which are usually remains a promising approach for the treatment of in the quiescent phase, are favored by the HSPC com- sickle cell disease and beta-thalassemia. Strategies ponent in extramedullary tissue, but proliferation is inhib- include targeting transcription factors that regulate ited. Additionally, anemia stress increases fetal to adult hemoglobin conversions, such as BCL11A, erythrocyte phagocytosis, and splenic macrophages KLF1, and MYB, or using epigenetic regulators such as promote CCL2 output, which recruits circulating mono- HDAC and LSD1 inhibitors. Gene therapy using lentiviral cytes and forms new hematopoietic islands in the vectors to express the β-globin gene or shRNA targeting spleen. Macrophages regulate the circulation of splenic BCL11A in hematopoietic stem cells has shown the 12 P. TANG AND H. WANG potential to permanently correct hemoglobinopathy. ORCID Gene editing using CRISPR/Cas9 to correct potential Huaquan Wang http://orcid.org/0000-0003-2402-2717 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- References agement of iron homeostasis with hepcidin modulators, Nandakumar SK, Ulirsch JC, Sankaran VG. Advances in small hepcidin, or TMPRSS6 inhibitors may help treat iron understanding erythropoiesis: evolving perspectives. overload in patients with transfusion-dependent thalas- Br J Haematol. 2016;173(2):206–218. DOI:10.1111/bjh. 13938 semia. Anti-inﬂammatory therapies such as selectin Dzierzak E, Philipsen S. Erythropoiesis: development inhibitors, anti-CXCR2, or iNKT cell blocking may alleviate and diﬀerentiation. Cold Spring Harb Perspect Med. vaso-blocking crises and organ damage in sickle cell 2013;3(4):011–601. disease. Enzyme or molecular replacement gene Yumine A, Fraser ST, Sugiyama D. Regulation of the therapy appears to hold promise for treating rare inher- embryonic erythropoietic niche: a future perspective. ited anemia such as pyruvate kinase deﬁciency and con- Blood Res. 2017;52(1):10–17. DOI:10.5045/br.2017.52.1.10 Yamane T. Cellular basis of embryonic hematopoiesis genital erythropoietic porphyria. and its implications in prenatal erythropoiesis. Int J For polycythemia vera, maintaining hematocrit Mol Sci. 2020;21(24):9346. DOI:10.3390/ijms21249346 targets of

Regulation of Erythropoiesis: Emerging Concepts and Implications (2023) PDF

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