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Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 27861

Special Issue Editors

Prof. Dr. Mariano Ostuni

E-Mail Website
Guest Editor
UMR_S1134 Integrated Biology of Red Blood Cell, University of Paris, UMR_S1134 Paris, France
Interests: erythrocyte; Red blood cell; erythropoiesis; mitochondria; anemia
Dr. Sarah Ducamp

E-Mail Website
Guest Editor
Department of Pathology Enders Research Building, Boston Children's Hospital, Boston, MA, USA
Interests: congenital sideroblastic anemias; erythropoiesis; heme biosynthesis; protoporphyrias

Special Issue Information

Dear Colleagues,

Red blood cells (RBC) are the most abundant human cells, playing crucial physiological functions as O2 and CO2 transport and exchange and pH homeostasis. Bone marrow produces 2.106 reticulocytes/sec, which will be released to the circulation and become mature RBC, having an average lifespan of 120 days before being cleared. Dysfunctions on the red cell production, red cell function or red cell elimination have deep consequences to health, and are responsible for several types of anemia, an emergent public health challenge.

This special issue aims to include different topics of the research on non-malignant hematology, including both basic and applied research investigating the mechanisms involved in physiology of erythroid differentiation as well as mature and senescent red blood cells.Unraveling these mechanisms will contribute to better understanding the pathophysiology of non-malignant hematological disease.

Research areas may include (but are not limited to) the following: erythrocyte function, erythropoiesis, organelle clearance, non-malignant hematological disease, and appropriate models and experimental approaches to study red blood cells and their production. Both original research articles and reviews on these topics are welcome.

Prof. Dr. Mariano Ostuni
Dr. Sarah Ducamp
Guest Editors

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

  • erythrocyte
  • reticulocyte
  • erythroblasts
  • erythropoiesis
  • anemia
  • red blood cell membranes
  • red blood cell lipids
  • enucleation
  • organelle clearance
  • erythroid cell lines

Published Papers (11 papers)

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Editorial

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3 pages, 203 KiB  
Editorial
Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell
by Sarah Ducamp and Mariano A. Ostuni
Int. J. Mol. Sci. 2023, 24(11), 9715; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119715 - 03 Jun 2023
Viewed by 843
Abstract
Red blood cells (RBC) are the most abundant cells in mammals [...] Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)

Research

Jump to: Editorial, Review

19 pages, 2787 KiB  
Article
Mechanosensitive Pannexin 1 Activity Is Modulated by Stomatin in Human Red Blood Cells
by Sarah Rougé, Sandrine Genetet, Maria Florencia Leal Denis, Michael Dussiot, Pablo Julio Schwarzbaum, Mariano Anibal Ostuni and Isabelle Mouro-Chanteloup
Int. J. Mol. Sci. 2022, 23(16), 9401; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169401 - 20 Aug 2022
Cited by 3 | Viewed by 1634
Abstract
Pannexin 1 (PANX1) was proposed to drive ATP release from red blood cells (RBCs) in response to stress conditions. Stomatin, a membrane protein regulating mechanosensitive channels, has been proposed to modulate PANX1 activity in non-erythroid cells. To determine whether stomatin modulates PANX1 activity [...] Read more.
Pannexin 1 (PANX1) was proposed to drive ATP release from red blood cells (RBCs) in response to stress conditions. Stomatin, a membrane protein regulating mechanosensitive channels, has been proposed to modulate PANX1 activity in non-erythroid cells. To determine whether stomatin modulates PANX1 activity in an erythroid context, we have (i) assessed the in situ stomatin-PANX1 interaction in RBCs, (ii) measured PANX1-stimulated activity in RBCs expressing stomatin or from OverHydrated Hereditary Stomatocytosis (OHSt) patients lacking stomatin, and in erythroid K562 cells invalidated for stomatin. Proximity Ligation Assay coupled with flow imaging shows 27.09% and 6.13% positive events in control and OHSt RBCs, respectively. The uptake of dyes 5(6)-Carboxyfluorescein (CF) and TO-PRO-3 was used to evaluate PANX1 activity. RBC permeability for CF is 34% and 11.8% in control and OHSt RBCs, respectively. PANX1 permeability for TO-PRO-3 is 35.72% and 18.42% in K562 stom+ and stom− clones, respectively. These results suggest an interaction between PANX1 and stomatin in human RBCs and show a significant defect in PANX1 activity in the absence of stomatin. Based on these results, we propose that stomatin plays a major role in opening the PANX1 pore by being involved in a caspase-independent lifting of autoinhibition. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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16 pages, 1455 KiB  
Article
Phagocytosis of Erythrocytes from Gaucher Patients Induces Phenotypic Modifications in Macrophages, Driving Them toward Gaucher Cells
by Lucie Dupuis, Margaux Chauvet, Emmanuelle Bourdelier, Michaël Dussiot, Nadia Belmatoug, Caroline Le Van Kim, Arnaud Chêne and Mélanie Franco
Int. J. Mol. Sci. 2022, 23(14), 7640; https://doi.org/10.3390/ijms23147640 - 11 Jul 2022
Cited by 5 | Viewed by 1927
Abstract
Gaucher disease (GD) is caused by glucocerebrosidase deficiency leading to the accumulation of sphingolipids in macrophages named “Gaucher’s Cells”. These cells are characterized by deregulated expression of cell surface markers, abnormal secretion of inflammatory cytokines, and iron sequestration. These cells are known to [...] Read more.
Gaucher disease (GD) is caused by glucocerebrosidase deficiency leading to the accumulation of sphingolipids in macrophages named “Gaucher’s Cells”. These cells are characterized by deregulated expression of cell surface markers, abnormal secretion of inflammatory cytokines, and iron sequestration. These cells are known to infiltrate tissues resulting in hematological manifestations, splenomegaly, and bone diseases. We have already demonstrated that Gaucher red blood cells exhibit altered properties suggesting their key role in GD clinical manifestations. We hypothesized that Gaucher’s erythrocytes could be prone to premature destruction by macrophages contributing to the formation of altered macrophages and Gaucher-like cells. We conducted in vitro experiments of erythrophagocytosis using erythrocytes from Gaucher’s patients or healthy donors. Our results showed an enhanced erythrophagocytosis of Gaucher red blood cells compared to healthy red blood cells, which is related to erythrocyte sphingolipids overload and reduced deformability. Importantly, we showed elevated expression of the antigen-presenting molecules CD1d and MHC-II and of the iron-regulator hepcidin in macrophages, as well as enhanced secretion of the pro-inflammatory cytokine IL-1β after phagocytosis of GD erythrocytes. These results strongly suggested that erythrophagocytosis in GD contribute to phenotypic modifications in macrophages. This present study shows that erythrocytes-macrophages interactions may be crucial in GD pathophysiology and pathogenesis. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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10 pages, 1305 KiB  
Communication
Ablation of Tmcc2 Gene Impairs Erythropoiesis in Mice
by Ranju Kumari, Tomasz M. Grzywa, Milena Małecka-Giełdowska, Karolina Tyszkowska, Robert Wrzesień, Olga Ciepiela, Dominika Nowis and Piotr Kaźmierczak
Int. J. Mol. Sci. 2022, 23(9), 5263; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095263 - 09 May 2022
Cited by 3 | Viewed by 2296
Abstract
(1) Background: Transcriptomic and proteomic studies provide a wealth of new genes potentially involved in red blood cell (RBC) maturation or implicated in the pathogenesis of anemias, necessitating validation of candidate genes in vivo; (2) Methods: We inactivated one such candidate, transmembrane and [...] Read more.
(1) Background: Transcriptomic and proteomic studies provide a wealth of new genes potentially involved in red blood cell (RBC) maturation or implicated in the pathogenesis of anemias, necessitating validation of candidate genes in vivo; (2) Methods: We inactivated one such candidate, transmembrane and coiled-coil domain 2 (Tmcc2) in mice, and analyzed the erythropoietic phenotype by light microscopy, transmission electron microscopy (TEM), and flow cytometry of erythrocytes and erythroid precursors; (3) Results: Tmcc2−/− pups presented pallor and reduced body weight due to the profound neonatal macrocytic anemia with numerous nucleated RBCs (nRBCs) and occasional multinucleated RBCs. Tmcc2−/− nRBCs had cytoplasmic intrusions into the nucleus and double membranes. Significantly fewer erythroid cells were enucleated. Adult knockouts were normocytic, mildly polycythemic, with active extramedullary erythropoiesis in the spleen. Altered relative content of different stage CD71+TER119+ erythroid precursors in the bone marrow indicated a severe defect of erythroid maturation at the polychromatic to orthochromatic transition stage; (4) Conclusions: Tmcc2 is required for normal erythropoiesis in mice. While several phenotypic features resemble congenital dyserythropoietic anemias (CDA) types II, III, and IV, the involvement of TMCC2 in the pathogenesis of CDA in humans remains to be determined. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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19 pages, 4714 KiB  
Article
Interactive Dynamics of Cell Volume and Cell Death in Human Erythrocytes Exposed to α-Hemolysin from Escherichia coli
by Nicolas A. Saffioti, Natalia Lauri, Lucia Cané, Rodolfo Gonzalez-Lebrero, Karina Alleva, Isabelle Mouro-Chanteloup, Mariano A. Ostuni, Vanesa Herlax and Pablo Julio Schwarzbaum
Int. J. Mol. Sci. 2022, 23(2), 872; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020872 - 14 Jan 2022
Cited by 6 | Viewed by 1647
Abstract
α-hemolysin (HlyA) of E. coli binds irreversibly to human erythrocytes and induces cell swelling, ultimately leading to hemolysis. We characterized the mechanism involved in water transport induced by HlyA and analyzed how swelling and hemolysis might be coupled. Osmotic water permeability (Pf [...] Read more.
α-hemolysin (HlyA) of E. coli binds irreversibly to human erythrocytes and induces cell swelling, ultimately leading to hemolysis. We characterized the mechanism involved in water transport induced by HlyA and analyzed how swelling and hemolysis might be coupled. Osmotic water permeability (Pf) was assessed by stopped-flow light scattering. Preincubation with HlyA strongly reduced Pf in control- and aquaporin 1-null red blood cells, although the relative Pf decrease was similar in both cell types. The dynamics of cell volume and hemolysis on RBCs was assessed by electrical impedance, light dispersion and hemoglobin release. Results show that HlyA induced erythrocyte swelling, which is enhanced by purinergic signaling, and is coupled to osmotic hemolysis. We propose a mathematical model of HlyA activity where the kinetics of cell volume and hemolysis in human erythrocytes depend on the flux of osmolytes across the membrane, and on the maximum volume that these cells can tolerate. Our results provide new insights for understanding signaling and cytotoxicity mediated by HlyA in erythrocytes. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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Review

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15 pages, 1139 KiB  
Review
Role of Macrophages in Sickle Cell Disease Erythrophagocytosis and Erythropoiesis
by Renata Sesti-Costa, Fernando F. Costa and Nicola Conran
Int. J. Mol. Sci. 2023, 24(7), 6333; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076333 - 28 Mar 2023
Cited by 7 | Viewed by 3384
Abstract
Sickle cell disease (SCD) is an inherited blood disorder caused by a β-globin gene point mutation that results in the production of sickle hemoglobin that polymerizes upon deoxygenation, causing the sickling of red blood cells (RBCs). RBC deformation initiates a sequence of events [...] Read more.
Sickle cell disease (SCD) is an inherited blood disorder caused by a β-globin gene point mutation that results in the production of sickle hemoglobin that polymerizes upon deoxygenation, causing the sickling of red blood cells (RBCs). RBC deformation initiates a sequence of events leading to multiple complications, such as hemolytic anemia, vaso-occlusion, chronic inflammation, and tissue damage. Macrophages participate in extravascular hemolysis by removing damaged RBCs, hence preventing the release of free hemoglobin and heme, and triggering inflammation. Upon erythrophagocytosis, macrophages metabolize RBC-derived hemoglobin, activating mechanisms responsible for recycling iron, which is then used for the generation of new RBCs to try to compensate for anemia. In the bone marrow, macrophages can create specialized niches, known as erythroblastic islands (EBIs), which regulate erythropoiesis. Anemia and inflammation present in SCD may trigger mechanisms of stress erythropoiesis, intensifying RBC generation by expanding the number of EBIs in the bone marrow and creating new ones in extramedullary sites. In the current review, we discuss the distinct mechanisms that could induce stress erythropoiesis in SCD, potentially shifting the macrophage phenotype to an inflammatory profile, and changing their supporting role necessary for the proliferation and differentiation of erythroid cells in the disease. The knowledge of the soluble factors, cell surface and intracellular molecules expressed by EBI macrophages that contribute to begin and end the RBC’s lifespan, as well as the understanding of their signaling pathways in SCD, may reveal potential targets to control the pathophysiology of the disease. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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11 pages, 340 KiB  
Review
Red Blood Cells: A Newly Described Partner in Central Retinal Vein Occlusion Pathophysiology?
by Sandrine Laurance, Mickaël Marin and Yves Colin
Int. J. Mol. Sci. 2023, 24(2), 1072; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021072 - 05 Jan 2023
Cited by 1 | Viewed by 1522
Abstract
Central retinal vein occlusion (CRVO) is a frequent retinal disorder inducing blindness due to the occlusion of the central vein of the retina. The primary cause of the occlusion remains to be identified leading to the lack of treatment. To date, current treatments [...] Read more.
Central retinal vein occlusion (CRVO) is a frequent retinal disorder inducing blindness due to the occlusion of the central vein of the retina. The primary cause of the occlusion remains to be identified leading to the lack of treatment. To date, current treatments mainly target the complications of the disease and do not target the primary dysfunctions. CRVO pathophysiology seems to be a multifactorial disorder; several studies did attempt to decipher the cellular and molecular mechanisms underlying the vessel obstruction, but no consensual mechanism has been found. The aim of the current review is to give an overview of CRVO pathophysiology and more precisely the role of the erythroid lineage. The review presents emerging data on red blood cell (RBC) functions besides their role as an oxygen transporter and how disturbance of RBC function could impact the whole vascular system. We also aim to gather new evidence of RBC involvement in CRVO occurrence. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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15 pages, 839 KiB  
Review
Erythropoiesis and Malaria, a Multifaceted Interplay
by Aurélie Dumarchey, Catherine Lavazec and Frédérique Verdier
Int. J. Mol. Sci. 2022, 23(21), 12762; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112762 - 23 Oct 2022
Cited by 3 | Viewed by 3353
Abstract
One of the major pathophysiologies of malaria is the development of anemia. Although hemolysis and splenic clearance are well described as causes of malarial anemia, abnormal erythropoiesis has been observed in malaria patients and may contribute significantly to anemia. The interaction between inadequate [...] Read more.
One of the major pathophysiologies of malaria is the development of anemia. Although hemolysis and splenic clearance are well described as causes of malarial anemia, abnormal erythropoiesis has been observed in malaria patients and may contribute significantly to anemia. The interaction between inadequate erythropoiesis and Plasmodium parasite infection, which partly occurs in the bone marrow, has been poorly investigated to date. However, recent findings may provide new insights. This review outlines clinical and experimental studies describing different aspects of ineffective erythropoiesis and dyserythropoiesis observed in malaria patients and in animal or in vitro models. We also highlight the various human and parasite factors leading to erythropoiesis disorders and discuss the impact that Plasmodium parasites may have on the suppression of erythropoiesis. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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14 pages, 327 KiB  
Review
Histone Deacetylases Function in the Control of Early Hematopoiesis and Erythropoiesis
by Pascal Vong, Hakim Ouled-Haddou and Loïc Garçon
Int. J. Mol. Sci. 2022, 23(17), 9790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179790 - 29 Aug 2022
Cited by 5 | Viewed by 1513
Abstract
Numerous studies have highlighted the role of post-translational modifications in the regulation of cell proliferation, differentiation and death. Among these modifications, acetylation modifies the physicochemical properties of proteins and modulates their activity, stability, localization and affinity for partner proteins. Through the deacetylation of [...] Read more.
Numerous studies have highlighted the role of post-translational modifications in the regulation of cell proliferation, differentiation and death. Among these modifications, acetylation modifies the physicochemical properties of proteins and modulates their activity, stability, localization and affinity for partner proteins. Through the deacetylation of a wide variety of functional and structural, nuclear and cytoplasmic proteins, histone deacetylases (HDACs) modulate important cellular processes, including hematopoiesis, during which different HDACs, by controlling gene expression or by regulating non-histone protein functions, act sequentially to provide a fine regulation of the differentiation process both in early hematopoietic stem cells and in more mature progenitors. Considering that HDAC inhibitors represent promising targets in cancer treatment, it is necessary to decipher the role of HDACs during hematopoiesis which could be impacted by these therapies. This review will highlight the main mechanisms by which HDACs control the hematopoietic stem cell fate, particularly in the erythroid lineage. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
19 pages, 21169 KiB  
Review
New Avenues of Heme Synthesis Regulation
by Amy E. Medlock and Harry A. Dailey
Int. J. Mol. Sci. 2022, 23(13), 7467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137467 - 05 Jul 2022
Cited by 6 | Viewed by 4959
Abstract
During erythropoiesis, there is an enormous demand for the synthesis of the essential cofactor of hemoglobin, heme. Heme is synthesized de novo via an eight enzyme-catalyzed pathway within each developing erythroid cell. A large body of data exists to explain the transcriptional regulation [...] Read more.
During erythropoiesis, there is an enormous demand for the synthesis of the essential cofactor of hemoglobin, heme. Heme is synthesized de novo via an eight enzyme-catalyzed pathway within each developing erythroid cell. A large body of data exists to explain the transcriptional regulation of the heme biosynthesis enzymes, but until recently much less was known about alternate forms of regulation that would allow the massive production of heme without depleting cellular metabolites. Herein, we review new studies focused on the regulation of heme synthesis via carbon flux for porphyrin synthesis to post-translations modifications (PTMs) that regulate individual enzymes. These PTMs include cofactor regulation, phosphorylation, succinylation, and glutathionylation. Additionally discussed is the role of the immunometabolite itaconate and its connection to heme synthesis and the anemia of chronic disease. These recent studies provide new avenues to regulate heme synthesis for the treatment of diseases including anemias and porphyrias. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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11 pages, 978 KiB  
Review
Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems
by Zuzana Macečková, Agáta Kubíčková, Juan Bautista De Sanctis and Marian Hajdúch
Int. J. Mol. Sci. 2022, 23(3), 1886; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031886 - 08 Feb 2022
Cited by 8 | Viewed by 3398
Abstract
Diamond-Blackfan anaemia (DBA) is a red blood cell aplasia that in the majority of cases is associated with ribosomal protein (RP) aberrations. However, the mechanism by which this disorder leads to such a specific phenotype remains unclear. Even more elusive is the reason [...] Read more.
Diamond-Blackfan anaemia (DBA) is a red blood cell aplasia that in the majority of cases is associated with ribosomal protein (RP) aberrations. However, the mechanism by which this disorder leads to such a specific phenotype remains unclear. Even more elusive is the reason why non-specific agents such as glucocorticosteroids (GCs), also known as glucocorticoids, are an effective therapy for DBA. In this review, we (1) explore why GCs are successful in DBA treatment, (2) discuss the effect of GCs on erythropoiesis, and (3) summarise the GC impact on crucial pathways deregulated in DBA. Furthermore, we show that GCs do not regulate DBA erythropoiesis via a single mechanism but more likely via several interdependent pathways. Full article
(This article belongs to the Special Issue Physiology of Red Cell Lineage: From Erythroblast Progenitors to Mature Red Blood Cell)
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