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Regulation of Erythropoiesis 2.0
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Regulation of Erythropoiesis 2.0

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 May 2021) | Viewed by 32006

Special Issue Editor

Prof. Dr. Chul Geun Kim

E-Mail Website
Guest 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 organelles, 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 models 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 been made, 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 pathophysiological mechanisms.

You can also view our first edition Special Issue and its publications at: https://www.mdpi.com/journal/ijms/special_issues/erythropoiesis.

Prof. Chul Geun Kim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Related Special Issue

Published Papers (6 papers)

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Review

27 pages, 1318 KiB  
Review
Industrially Compatible Transfusable iPSC-Derived RBCs: Progress, Challenges and Prospective Solutions
by Zhong Ri Lim, Svetlan Vassilev, Yew Wai Leong, Jing Wen Hang, Laurent Rénia, Benoit Malleret and Steve Kah-Weng Oh
Int. J. Mol. Sci. 2021, 22(18), 9808; https://doi.org/10.3390/ijms22189808 - 10 Sep 2021
Cited by 10 | Viewed by 7709
Abstract
Amidst the global shortfalls in blood supply, storage limitations of donor blood and the availability of potential blood substitutes for transfusion applications, society has pivoted towards in vitro generation of red blood cells (RBCs) as a means to solve these issues. Many conventional [...] Read more.
Amidst the global shortfalls in blood supply, storage limitations of donor blood and the availability of potential blood substitutes for transfusion applications, society has pivoted towards in vitro generation of red blood cells (RBCs) as a means to solve these issues. Many conventional research studies over the past few decades have found success in differentiating hematopoietic stem and progenitor cells (HSPCs) from cord blood, adult bone marrow and peripheral blood sources. More recently, techniques that involve immortalization of erythroblast sources have also gained traction in tackling this problem. However, the RBCs generated from human induced pluripotent stem cells (hiPSCs) still remain as the most favorable solution due to many of its added advantages. In this review, we focus on the breakthroughs for high-density cultures of hiPSC-derived RBCs, and highlight the major challenges and prospective solutions throughout the whole process of erythropoiesis for hiPSC-derived RBCs. Furthermore, we elaborate on the recent advances and techniques used to achieve cost-effective, high-density cultures of GMP-compliant RBCs, and on their relevant novel applications after downstream processing and purification. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis 2.0)
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14 pages, 1085 KiB  
Review
The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization
by Zuzana Tóthová, Martina Šemeláková, Zuzana Solárová, Jana Tomc, Nataša Debeljak and Peter Solár
Int. J. Mol. Sci. 2021, 22(14), 7682; https://doi.org/10.3390/ijms22147682 - 19 Jul 2021
Cited by 37 | Viewed by 4915
Abstract
Erythropoietin (EPO) is a glycoprotein cytokine known for its pleiotropic effects on various types of cells and tissues. EPO and its receptor EPOR trigger signaling cascades JAK2/STAT5, MAPK, and PI3K/AKT that are interconnected and irreplaceable for cell survival. In this article, we describe [...] Read more.
Erythropoietin (EPO) is a glycoprotein cytokine known for its pleiotropic effects on various types of cells and tissues. EPO and its receptor EPOR trigger signaling cascades JAK2/STAT5, MAPK, and PI3K/AKT that are interconnected and irreplaceable for cell survival. In this article, we describe the role of the MAPK and PI3K/AKT signaling pathways during red blood cell formation as well as in non-hematopoietic tissues and tumor cells. Although the central framework of these pathways is similar for most of cell types, there are some stage-specific, tissue, and cell-lineage differences. We summarize the current state of research in this field, highlight the novel members of EPO-induced PI3K and MAPK signaling, and in this respect also the differences between erythroid and non-erythroid cells. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis 2.0)
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Graphical abstract

13 pages, 873 KiB  
Review
STAT5 as a Key Protein of Erythropoietin Signalization
by Zuzana Tóthová, Jana Tomc, Nataša Debeljak and Peter Solár
Int. J. Mol. Sci. 2021, 22(13), 7109; https://doi.org/10.3390/ijms22137109 - 01 Jul 2021
Cited by 20 | Viewed by 7539
Abstract
Erythropoietin (EPO) acts on multiple tissues through its receptor EPOR, a member of a cytokine class I receptor superfamily with pleiotropic effects. The interaction of EPO and EPOR triggers the activation of several signaling pathways that induce erythropoiesis, including JAK2/STAT5, PI3K/AKT, and MAPK. [...] Read more.
Erythropoietin (EPO) acts on multiple tissues through its receptor EPOR, a member of a cytokine class I receptor superfamily with pleiotropic effects. The interaction of EPO and EPOR triggers the activation of several signaling pathways that induce erythropoiesis, including JAK2/STAT5, PI3K/AKT, and MAPK. The canonical EPOR/JAK2/STAT5 pathway is a known regulator of differentiation, proliferation, and cell survival of erythroid progenitors. In addition, its role in the protection of other cells, including cancer cells, is under intense investigation. The involvement of EPOR/JAK2/STAT5 in other processes such as mRNA splicing, cytoskeleton reorganization, and cell metabolism has been recently described. The transcriptomics, proteomics, and epigenetic studies reviewed in this article provide a detailed understanding of EPO signalization. Advances in this area of research may be useful for improving the efficacy of EPO therapy in hematologic disorders, as well as in cancer treatment. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis 2.0)
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16 pages, 670 KiB  
Review
Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis
by Jana Tomc and Nataša Debeljak
Int. J. Mol. Sci. 2021, 22(13), 7074; https://doi.org/10.3390/ijms22137074 - 30 Jun 2021
Cited by 11 | Viewed by 3096
Abstract
Erythropoiesis is regulated by several factors, including the oxygen-sensing pathway as the main regulator of erythropoietin (EPO) synthesis in the kidney. The release of EPO from the kidney and its binding to the EPO receptor (EPOR) on erythrocyte progenitor cells in the bone [...] Read more.
Erythropoiesis is regulated by several factors, including the oxygen-sensing pathway as the main regulator of erythropoietin (EPO) synthesis in the kidney. The release of EPO from the kidney and its binding to the EPO receptor (EPOR) on erythrocyte progenitor cells in the bone marrow results in increased erythropoiesis. Any imbalance in these homeostatic mechanisms can lead to dysregulated erythropoiesis and hematological disorders. For example, mutations in genes encoding key players of oxygen-sensing pathway and regulation of EPO production (HIF-EPO pathway), namely VHL, EGLN, EPAS1 and EPO, are well known causative factors that contribute to the development of erythrocytosis. We aimed to investigate additional molecular mechanisms involved in the HIF-EPO pathway that correlate with erythropoiesis. To this end, we conducted an extensive literature search and used several in silico tools. We identified genes encoding transcription factors and proteins that control transcriptional activation or repression; genes encoding kinases, deacetylases, methyltransferases, conjugating enzymes, protein ligases, and proteases involved in post-translational modifications; and genes encoding nuclear transport receptors that regulate nuclear transport. All these genes may modulate the stability or activity of HIF2α and its partners in the HIF-EPO pathway, thus affecting EPO synthesis. The theoretical information we provide in this work can be a valuable tool for a better understanding of one of the most important regulatory pathways in the process of erythropoiesis. This knowledge is necessary to discover the causative factors that may contribute to the development of hematological diseases and improve current diagnostic and treatment solutions in this regard. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis 2.0)
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17 pages, 8210 KiB  
Review
The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance
by Simon Grootendorst, Jonathan de Wilde, Birgit van Dooijeweert, Annelies van Vuren, Wouter van Solinge, Roger Schutgens, Richard van Wijk and Marije Bartels
Int. J. Mol. Sci. 2021, 22(4), 2204; https://doi.org/10.3390/ijms22042204 - 23 Feb 2021
Cited by 5 | Viewed by 3381
Abstract
Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due [...] Read more.
Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis 2.0)
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15 pages, 1005 KiB  
Review
Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia
by Sarah Parisi, Carlo Finelli, Antonietta Fazio, Alessia De Stefano, Sara Mongiorgi, Stefano Ratti, Alessandra Cappellini, Anna Maria Billi, Lucio Cocco, Matilde Y. Follo and Lucia Manzoli
Int. J. Mol. Sci. 2021, 22(2), 827; https://doi.org/10.3390/ijms22020827 - 15 Jan 2021
Cited by 12 | Viewed by 4165
Abstract
Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on [...] Read more.
Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia. Full article
(This article belongs to the Special Issue Regulation of Erythropoiesis 2.0)
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