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Regulation of Erythropoiesis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 52532

Special Issue Editor

Department of Life Science, Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea
Interests: transcriptional regulation; transcription factors; chromatin remodeling complexes; cell fate decision; erythropoiesis; cancer stem cells; anticancer drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Approximately 84% of the cells in the human body are red blood cells. Erythropoiesis is the complex process that produces mature red blood cells (erythrocytes) from erythropoietic stem cells, and mature red blood cells in mammals uniquely lack a cell nucleus and most organelle, with some exceptions in some salamanders and fish. Genetic diseases, such as sickle cell anemia and hereditary persistence of fetal hemoglobin (HPFH) and erythroleukemia, have been studied as a model for gene expression control and for molecular genetic understanding and treatment development. However, although considerable advances in the understanding of erythropoiesis and hemoglobin switching have occurred, the fundamental molecular mechanism of the regulation of erythropoiesis and globin switching is still not understood

This Special Issue on the regulation of erythropoiesis will include a selection of original papers and reviews focused on genetic and cellular bases and molecular mechanisms of erythroid differentiation and globin switching, including epigenetic connections between the gene regulatory network and chromatin dynamics, cell signaling, recent progress in single cell genomics, and various new pathophysiologic mechanisms.

Prof. Chul Geun Kim
Guest Editor

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Keywords

  • erythropoiesis
  • hemoglobin switching
  • gene regulatory network
  • epigenetics
  • chromatin dynamics
  • cell signaling
  • single cell genomics
  • pathophysiologic mechanisms

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Published Papers (11 papers)

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Research

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12 pages, 1824 KiB  
Article
Impact of Erythropoietin Production by Erythroblastic Island Macrophages on Homeostatic Murine Erythropoiesis
by Genève Perron-Deshaies, Philippe St-Louis, Hugo Romero and Tatiana Scorza
Int. J. Mol. Sci. 2020, 21(23), 8930; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238930 - 25 Nov 2020
Cited by 5 | Viewed by 2335
Abstract
Erythropoietin (EPO) is an essential hormone for erythropoiesis, protecting differentiating erythroblasts against apoptosis. EPO has been largely studied in stress or pathological conditions but its regulatory role in steady state erythropoiesis has been less documented. Herein, we report production of EPO by bone [...] Read more.
Erythropoietin (EPO) is an essential hormone for erythropoiesis, protecting differentiating erythroblasts against apoptosis. EPO has been largely studied in stress or pathological conditions but its regulatory role in steady state erythropoiesis has been less documented. Herein, we report production of EPO by bone marrow-derived macrophages (BMDM) in vitro, and its further enhancement in BMDM conditioned with media from apoptotic cells. Confocal microscopy confirmed EPO production in erythroblastic island (EBI)-associated macrophages, and analysis of mice depleted of EBI macrophages by clodronate liposomes revealed drops in EPO levels in bone marrow (BM) cell lysates, and decreased percentages of EPO-responsive erythroblasts in the BM. We hypothesize that EBI macrophages are an in-situ source of EPO and sustain basal erythropoiesis in part through its secretion. To study this hypothesis, mice were injected with clodronate liposomes and were supplied with exogenous EPO (1–10 IU/mouse) to evaluate potential rescue of the deficiency in erythroid cells. Our results show that at doses of 5 and 10 IU, EPO significantly rescues BM steady state erythropoiesis in mice deficient of macrophages. We propose existence of a mechanism by which EBI macrophages secrete EPO in response to apoptotic erythroblasts, which is in turn controlled by the numbers of erythroid precursors generated. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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14 pages, 2443 KiB  
Article
A Hypoxia-Inducible Factor Stabilizer Improves Hematopoiesis and Iron Metabolism Early after Administration to Treat Anemia in Hemodialysis Patients
by Chie Ogawa, Ken Tsuchiya, Naohisa Tomosugi and Kunimi Maeda
Int. J. Mol. Sci. 2020, 21(19), 7153; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197153 - 28 Sep 2020
Cited by 16 | Viewed by 4571
Abstract
Roxadustat (Rox), a hypoxia-inducible factor (HIF) stabilizer, is now available for the treatment of anemia in hemodialysis (HD) patients. To investigate hematopoietic effect and iron metabolism, this study involved 30 HD patients who were initially treated with darbepoetin (DA), a conventional erythropoietin-stimulating agent, [...] Read more.
Roxadustat (Rox), a hypoxia-inducible factor (HIF) stabilizer, is now available for the treatment of anemia in hemodialysis (HD) patients. To investigate hematopoietic effect and iron metabolism, this study involved 30 HD patients who were initially treated with darbepoetin (DA), a conventional erythropoietin-stimulating agent, and then switched to Rox. We measured erythrocyte, reticulocyte indices, and iron-related factors at every HD during the first two weeks after the treatment switch (Days 0–14) and again on Days 21 and 28. We measured erythropoietin (EPO) concentration every week and examined their changes from Day-0 values. The same variables were measured in 15 HD patients who continued DA at every HD for one week. Iron-related factors were also measured on Days 14 and 28. In the Rox group, hepcidin significantly decreased from Day 2. The reticulocyte hemoglobin content (CHr) significantly increased on Day 4, but decreased with a significant increase in reticulocyte count from Day 7. Log10(serum ferritin) significantly decreased after Day 11. Log10(EPO concentration) was lower at all time points. Compared with the DA group, the Rox group showed significant differences in all variables except CHr. These results suggest that Rox improves hematopoiesis and iron metabolism early after administration independent of EPO concentration. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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19 pages, 2681 KiB  
Article
Role of Plasma Gelsolin Protein in the Final Stage of Erythropoiesis and in Correction of Erythroid Dysplasia In Vitro
by So Yeon Han, Eun Mi Lee, Suyeon Kim, Amy M. Kwon and Eun Jung Baek
Int. J. Mol. Sci. 2020, 21(19), 7132; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197132 - 27 Sep 2020
Cited by 3 | Viewed by 2498
Abstract
Gelsolin, an actin-remodeling protein, is involved in cell motility, cytoskeletal remodeling, and cytokinesis and is abnormally expressed in many cancers. Recently, human recombinant plasma gelsolin protein (pGSN) was reported to have important roles in cell cycle and maturation of primary erythroblasts. However, the [...] Read more.
Gelsolin, an actin-remodeling protein, is involved in cell motility, cytoskeletal remodeling, and cytokinesis and is abnormally expressed in many cancers. Recently, human recombinant plasma gelsolin protein (pGSN) was reported to have important roles in cell cycle and maturation of primary erythroblasts. However, the role of human plasma gelsolin in late stage erythroblasts prior to enucleation and putative clinical relevance in patients with myelodysplastic syndrome (MDS) and hemato-oncologic diseases have not been reported. Polychromatic and orthochromatic erythroblasts differentiated from human cord blood CD34+ cells, and human bone marrow (BM) cells derived from patients with MDS, were cultured in serum-free medium containing pGSN. Effects of pGSN on mitochondria, erythroid dysplasia, and enucleation were assessed in cellular and transcriptional levels. With pGSN treatment, terminal maturation at the stage of poly- and ortho-chromatic erythroblasts was enhanced, with higher numbers of orthochromatic erythroblasts and enucleated red blood cells (RBCs). pGSN also significantly decreased dysplastic features of cell morphology. Moreover, we found that patients with MDS with multi-lineage dysplasia or with excess blasts-1 showed significantly decreased expression of gelsolin mRNA (GSN) in their peripheral blood. When BM erythroblasts of MDS patients were cultured with pGSN, levels of mRNA transcripts related to terminal erythropoiesis and enucleation were markedly increased, with significantly decreased erythroid dysplasia. Moreover, pGSN treatment enhanced mitochondrial transmembrane potential that is unregulated in MDS and cultured cells. Our findings demonstrate a key role for plasma gelsolin in erythropoiesis and in gelsolin-depleted MDS patients, and raises the possibility that pGSN administration may promote erythropoiesis in erythroid dysplasia. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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11 pages, 1700 KiB  
Article
RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway
by Gianluca De Rosa, Immacolata Andolfo, Roberta Marra, Francesco Manna, Barbara Eleni Rosato, Achille Iolascon and Roberta Russo
Int. J. Mol. Sci. 2020, 21(15), 5577; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155577 - 04 Aug 2020
Cited by 8 | Viewed by 2965
Abstract
Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is [...] Read more.
Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B-silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B-silenced K562 cells with RAP-011, a “murinized” ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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Review

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16 pages, 997 KiB  
Review
Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs
by Filomena Longo, Andrea Piolatto, Giovanni Battista Ferrero and Antonio Piga
Int. J. Mol. Sci. 2021, 22(13), 7229; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137229 - 05 Jul 2021
Cited by 19 | Viewed by 5576
Abstract
β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently [...] Read more.
β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-β superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in β-thalassaemia from bench to bedside. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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16 pages, 1633 KiB  
Review
Transferrin Receptors in Erythropoiesis
by Cyrielle Richard and Frédérique Verdier
Int. J. Mol. Sci. 2020, 21(24), 9713; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249713 - 19 Dec 2020
Cited by 23 | Viewed by 4461
Abstract
Erythropoiesis is a highly dynamic process giving rise to red blood cells from hematopoietic stem cells present in the bone marrow. Red blood cells transport oxygen to tissues thanks to the hemoglobin comprised of α- and β-globin chains and of iron-containing hemes. Erythropoiesis [...] Read more.
Erythropoiesis is a highly dynamic process giving rise to red blood cells from hematopoietic stem cells present in the bone marrow. Red blood cells transport oxygen to tissues thanks to the hemoglobin comprised of α- and β-globin chains and of iron-containing hemes. Erythropoiesis is the most iron-consuming process to support hemoglobin production. Iron delivery is mediated via transferrin internalization by the endocytosis of transferrin receptor type 1 (TFR1), one of the most abundant membrane proteins of erythroblasts. A second transferrin receptor—TFR2—associates with the erythropoietin receptor and has been implicated in the regulation of erythropoiesis. In erythroblasts, both transferrin receptors adopt peculiarities such as an erythroid-specific regulation of TFR1 and a trafficking pathway reliant on TFR2 for iron. This review reports both trafficking and signaling functions of these receptors and reassesses the debated role of TFR2 in erythropoiesis in the light of recent findings. Potential therapeutic uses targeting the transferrin-TFR1 axis or TFR2 in hematological disorders are also discussed. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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12 pages, 927 KiB  
Review
Cellular Basis of Embryonic Hematopoiesis and Its Implications in Prenatal Erythropoiesis
by Toshiyuki Yamane
Int. J. Mol. Sci. 2020, 21(24), 9346; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249346 - 08 Dec 2020
Cited by 8 | Viewed by 3420
Abstract
Primitive erythrocytes are the first hematopoietic cells observed during ontogeny and are produced specifically in the yolk sac. Primitive erythrocytes express distinct hemoglobins compared with adult erythrocytes and circulate in the blood in the nucleated form. Hematopoietic stem cells produce adult-type (so-called definitive) [...] Read more.
Primitive erythrocytes are the first hematopoietic cells observed during ontogeny and are produced specifically in the yolk sac. Primitive erythrocytes express distinct hemoglobins compared with adult erythrocytes and circulate in the blood in the nucleated form. Hematopoietic stem cells produce adult-type (so-called definitive) erythrocytes. However, hematopoietic stem cells do not appear until the late embryonic/early fetal stage. Recent studies have shown that diverse types of hematopoietic progenitors are present in the yolk sac as well as primitive erythroblasts. Multipotent hematopoietic progenitors that arose in the yolk sac before hematopoietic stem cells emerged likely fill the gap between primitive erythropoiesis and hematopoietic stem-cell-originated definitive erythropoiesis and hematopoiesis. In this review, we discuss the cellular origin of primitive erythropoiesis in the yolk sac and definitive hematopoiesis in the fetal liver. We also describe mechanisms for developmental switches that occur during embryonic and fetal erythropoiesis and hematopoiesis, particularly focusing on recent studies performed in mice. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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22 pages, 1350 KiB  
Review
Regulating the Regulators: The Role of Histone Deacetylase 1 (HDAC1) in Erythropoiesis
by Min Young Kim, Bowen Yan, Suming Huang and Yi Qiu
Int. J. Mol. Sci. 2020, 21(22), 8460; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228460 - 11 Nov 2020
Cited by 19 | Viewed by 4942
Abstract
Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Class I deacetylase HDAC1/2 often associates with repressor complexes, such as Sin3 (Switch Independent 3), NuRD (Nucleosome remodeling and deacetylase) and CoREST (Corepressor of RE1 silencing transcription factor) complexes. It has [...] Read more.
Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Class I deacetylase HDAC1/2 often associates with repressor complexes, such as Sin3 (Switch Independent 3), NuRD (Nucleosome remodeling and deacetylase) and CoREST (Corepressor of RE1 silencing transcription factor) complexes. It has been shown that HDAC1 interacts with and modulates all essential transcription factors for erythropoiesis. During erythropoiesis, histone deacetylase activity is dramatically reduced. Consistently, inhibition of HDAC activity promotes erythroid differentiation. The reduction of HDAC activity not only results in the activation of transcription activators such as GATA-1 (GATA-binding factor 1), TAL1 (TAL BHLH Transcription Factor 1) and KLF1 (Krüpple-like factor 1), but also represses transcription repressors such as PU.1 (Putative oncogene Spi-1). The reduction of histone deacetylase activity is mainly through HDAC1 acetylation that attenuates HDAC1 activity and trans-repress HDAC2 activity through dimerization with HDAC1. Therefore, the acetylation of HDAC1 can convert the corepressor complex to an activator complex for gene activation. HDAC1 also can deacetylate non-histone proteins that play a role on erythropoiesis, therefore adds another layer of gene regulation through HDAC1. Clinically, it has been shown HDACi can reactivate fetal globin in adult erythroid cells. This review will cover the up to date research on the role of HDAC1 in modulating key transcription factors for erythropoiesis and its clinical relevance. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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18 pages, 998 KiB  
Review
Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis
by Deepika Watts, Diana Gaete, Diego Rodriguez, David Hoogewijs, Martina Rauner, Sundary Sormendi and Ben Wielockx
Int. J. Mol. Sci. 2020, 21(21), 8131; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218131 - 30 Oct 2020
Cited by 25 | Viewed by 11941
Abstract
Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is [...] Read more.
Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)–EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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15 pages, 798 KiB  
Review
An Overview of Different Strategies to Recreate the Physiological Environment in Experimental Erythropoiesis
by Cécile Deleschaux, Martina Moras, Sophie D. Lefevre and Mariano A. Ostuni
Int. J. Mol. Sci. 2020, 21(15), 5263; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155263 - 24 Jul 2020
Cited by 8 | Viewed by 3003
Abstract
Human erythropoiesis is a complex process leading to the production of mature, enucleated erythrocytes (RBCs). It occurs mainly at bone marrow (BM), where hematopoietic stem cells (HSCs) are engaged in the early erythroid differentiation to commit into erythroid progenitor cells (burst-forming unit erythroid [...] Read more.
Human erythropoiesis is a complex process leading to the production of mature, enucleated erythrocytes (RBCs). It occurs mainly at bone marrow (BM), where hematopoietic stem cells (HSCs) are engaged in the early erythroid differentiation to commit into erythroid progenitor cells (burst-forming unit erythroid (BFU-E) and colony-forming unit erythroid (CFU-E)). Then, during the terminal differentiation, several erythropoietin-induced signaling pathways trigger the differentiation of CFU-E on successive stages from pro-erythroblast to reticulocytes. The latter are released into the circulation, finalizing their maturation into functional RBCs. This process is finely regulated by the physiological environment including the erythroblast-macrophage interaction in the erythroblastic island (EBI). Several human diseases have been associated with ineffective erythropoiesis, either by a defective or an excessive production of RBCs, as well as an increase or a hemoglobinization defect. Fully understanding the production of mature red blood cells is crucial for the comprehension of erythroid pathologies as well as to the field of transfusion. Many experimental approaches have been carried out to achieve a complete differentiation in vitro to produce functional biconcave mature RBCs. However, the various protocols usually fail to achieve enough quantities of completely mature RBCs. In this review, we focus on the evolution of erythropoiesis studies over the years, taking special interest in efforts that were made to include the microenvironment and erythroblastic islands paradigm. These more physiological approaches will contribute to a deeper comprehension of erythropoiesis, improve the treatment of dyserythropoietic disorders, and break through the barriers in massive RBCs production for transfusion. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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21 pages, 2034 KiB  
Review
Role of Extrinsic Apoptotic Signaling Pathway during Definitive Erythropoiesis in Normal Patients and in Patients with β-Thalassemia
by Olga Raducka-Jaszul, Dżamila M. Bogusławska, Natalia Jędruchniewicz and Aleksander F. Sikorski
Int. J. Mol. Sci. 2020, 21(9), 3325; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093325 - 08 May 2020
Cited by 16 | Viewed by 4904
Abstract
Apoptosis is a process of programmed cell death which has an important role in tissue homeostasis and in the control of organism development. Here, we focus on information concerning the role of the extrinsic apoptotic pathway in the control of human erythropoiesis. We [...] Read more.
Apoptosis is a process of programmed cell death which has an important role in tissue homeostasis and in the control of organism development. Here, we focus on information concerning the role of the extrinsic apoptotic pathway in the control of human erythropoiesis. We discuss the role of tumor necrosis factor α (TNFα), tumor necrosis factor ligand superfamily member 6 (FasL), tumor necrosis factor-related apoptosis-inducing (TRAIL) and caspases in normal erythroid maturation. We also attempt to initiate a discussion on the observations that mature erythrocytes contain most components of the receptor-dependent apoptotic pathway. Finally, we point to the role of the extrinsic apoptotic pathway in ineffective erythropoiesis of different types of β-thalassemia. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis)
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