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Molecular Research of Regulation of Red Blood Cells in Health, Hereditary or Acquired Diseases

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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: 25 May 2024 | Viewed by 5337

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Prof. Dr. Jean-Luc Wautier

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Faculté de Médecine, Université Denis Diderot Paris Cité, 75013 Paris, France
Interests: diabetes; hemostasis; coagulation; vascular physiology; glycation; hematology; dyserythropoiesis
Special Issues, Collections and Topics in MDPI journals

Dr. Marie-Paule Wautier

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Guest Editor

Faculté de Médecine, Université Denis Diderot Paris Cité, 75013 Paris, France
Interests: cellular biology; cell signaling; cell adhesion; cell proliferation; angiogenesis; diabetes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mammals and humans are oxygen-dependent organisms. Oxygen transport to organs and tissues is safely mediated by red blood cells. Hematopoietic stem cells proliferate and differentiate, leading to different blood cells: erythrocytes, leukocytes, and platelets. Erythropoiesis is strictly controlled by the bone marrow environment and growth factors, in particular, erythropoietin. Using one of the first microscopes, Jan Swammerdam (1658) and Antoni van Leeuwenhoek (1695) described red blood cells (RBCs). Anemia has been previously defined according to clinical features and associated with RBC mass reduction. During the last few centuries, significant progress has been made. After clinical and histological observation, the physiology of gas exchange and biochemical analysis of hemoglobin in cell culture allowed an understanding of the mechanisms responsible for diseases linked to abnormal cell production or clearance from the circulating blood.

In human red blood cells (RBCs), count and hemoglobin levels are relatively stable. RBCs are produced and remain circulating in blood vessels for approximatly 100 days. Erythropoiesis is dependent on several factors, including oxygen concentration, gene mutation, and nutritional factors. The most frequent causes of acquired anemia are hemorrhages and iron or vitamin deficiency. From the initial description of thalassemia, several hemoglobinopathies were discovered worldwide, with sickle-cell disease frequent in African populations. RBC enzyme mutations, such as glucose-6-phosphate dehydrogenase and pyruvate kinase, were observed as clusters in different countries. Genetic characterization, responsible for previously described RBC diseases such as spherocytosis, elliptocytosis, sideroblastic anemia, and various dyserythropoiesis syndromes, has been elucidated. The development of blood transfusions and treatment by drugs containing iron or vitamins has improved the clinical management of patients suffering from anemia. Blood marrow transplantation has become possible in some cases of hereditary diseases but remains limited for technical and financial reasons. The myeloproliferative syndrome may include polycythemia vera, but polycythemia may also be secondary to oxygen reduction or excessive erythropoietin production by tumor cells. Proliferative disorders benefit from the progress of chemotherapy. Genetic therapy has made substantial progress but is applied to orphan diseases according to the complexity of the method.

This Special Issue encourages the submission of manuscripts that provide novel and molecular insights and papers that report significant advances in this field.

Prof. Dr. Jean-Luc Wautier
Dr. Marie-Paule Wautier
Guest Editors

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Keywords

red blood cells
erythropoiesis
oxygen carrier
hemoglobin
thalassemia
sickle cell disease
dyserythropoiesis

Published Papers (5 papers)

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Research

12 pages, 7835 KiB

Open AccessArticle

Stress-Induced Changes in Nucleocytoplasmic Localization of Crucial Factors in Gene Expression Regulation

by Ali Khamit, Payal Chakraborty, Szabolcs Zahorán, Zoltán Villányi, Hajnalka Orvos and Edit Hermesz

Int. J. Mol. Sci. 2024, 25(7), 3895; https://doi.org/10.3390/ijms25073895 - 31 Mar 2024

Viewed by 758

Abstract

This study investigates the toxic effect of harmful materials, unfiltered by the placenta, on neonatal umbilical cord (UC) vessels, focusing on stress-induced adaptations in transcriptional and translational processes. It aims to analyze changes in pathways related to mRNA condensate formation, transcriptional regulation, and DNA damage response under maternal smoking-induced stress. UC vessels from neonates born to smoking (Sm) and nonsmoking mothers (Ctr) were examined. Immunofluorescence staining and confocal microscopy assessed the localization of key markers, including Transcription Complex Subunit 1 (CNOT1) and the largest subunit of RNA polymerase II enzyme (RPB1). Additionally, markers of DNA damage response, such as Poly(ADP-ribose) polymerase-1, were evaluated. In Sm samples, dissolution of CNOT1 granules in UC vessels was observed, potentially aiding stalled translation and enhancing transcription via RPB1 assembly and translocation. Control vessels showed predominant cytoplasmic RPB1 localization. Despite adaptive responses, Sm endothelial cells exhibited significant damage, indicated by markers like Poly(ADP-ribose) polymerase-1. Ex vivo metal treatment on control vessels mirrored Sm sample alterations, emphasizing marker roles in cell survival under toxic exposure. Maternal smoking induces specific molecular adaptations in UC vessels, affecting mRNA condensate formation, transcriptional regulation, and DNA damage response pathways. Understanding these intricate molecular mechanisms could inform interventions to improve neonatal health outcomes and mitigate adverse effects of toxic exposure during pregnancy. Full article

(This article belongs to the Special Issue Molecular Research of Regulation of Red Blood Cells in Health, Hereditary or Acquired Diseases)

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12 pages, 1038 KiB

Open AccessArticle

Reticulocyte Antioxidant Enzymes mRNA Levels versus Reticulocyte Maturity Indices in Hereditary Spherocytosis, β-Thalassemia and Sickle Cell Disease

by Daniela Melo, Fátima Ferreira, Maria José Teles, Graça Porto, Susana Coimbra, Susana Rocha and Alice Santos-Silva

Int. J. Mol. Sci. 2024, 25(4), 2159; https://doi.org/10.3390/ijms25042159 - 10 Feb 2024

Viewed by 642

Abstract

The antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and peroxiredoxin 2 (Prx2) are particularly important in erythroid cells. Reticulocytes and other erythroid precursors may adapt their biosynthetic mechanisms to cell defects or to changes in the bone marrow environment. Our aim was to perform a comparative study of the mRNA levels of CAT, GPX1, PRDX2 and SOD1 in reticulocytes from healthy individuals and from patients with hereditary spherocytosis (HS), sickle cell disease (SCD) and β-thalassemia (β-thal), and to study the association between their transcript levels and the reticulocyte maturity indices. In controls, the enzyme mRNA levels were significantly correlated with reticulocyte maturity indices for all genes except for SOD1. HS, SCD and β-thal patients showed younger reticulocytes, with higher transcript levels of all enzymes, although with different patterns. β-thal and HS showed similar reticulocyte maturity, with different enzyme mRNA levels; SCD and HS, with different reticulocyte maturity, presented similar enzyme mRNA levels. Our data suggest that the transcript profile for these antioxidant enzymes is not entirely related to reticulocyte maturity; it appears to also reflect adaptive mechanisms to abnormal erythropoiesis and/or to altered erythropoietic environments, leading to reticulocytes with distinct antioxidant potential according to each anemia. Full article

(This article belongs to the Special Issue Molecular Research of Regulation of Red Blood Cells in Health, Hereditary or Acquired Diseases)

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21 pages, 3051 KiB

Open AccessArticle

Hereditary Spherocytosis: Can Next-Generation Sequencing of the Five Most Frequently Affected Genes Replace Time-Consuming Functional Investigations?

by Friederike Häuser, Heidi Rossmann, Anke Adenaeuer, Annette Shrestha, Dana Marandiuc, Claudia Paret, Jörg Faber, Karl J. Lackner, Bernhard Lämmle and Olaf Beck

Int. J. Mol. Sci. 2023, 24(23), 17021; https://doi.org/10.3390/ijms242317021 - 30 Nov 2023

Viewed by 846

Abstract

Congenital defects of the erythrocyte membrane are common in northern Europe and all over the world. The resulting diseases, for example, hereditary spherocytosis (HS), are often underdiagnosed, partly due to their sometimes mild and asymptomatic courses. In addition to a broad clinical spectrum, this is also due to the occasionally complex diagnostics that are not available to every patient. To test whether next-generation sequencing (NGS) could replace time-consuming spherocytosis-specific functional tests, 22 consecutive patients with suspected red cell membranopathy underwent functional blood tests. We were able to identify the causative genetic defect in all patients with suspected HS who underwent genetic testing (n = 17). The sensitivity of the NGS approach, which tests five genes (ANK1 (gene product: ankyrin1), EPB42 (erythrocyte membrane protein band4.2), SLC4A1 (band3), SPTA1 (α-spectrin), and SPTB (β-spectrin)), was 100% (95% confidence interval: 81.5–100.0%). The major advantage of genetic testing in the paediatric setting is the small amount of blood required (<200 µL), and compared to functional assays, sample stability is not an issue. The combination of medical history, basic laboratory parameters, and an NGS panel with five genes is sufficient for diagnosis in most cases. Only in rare cases, a more comprehensive functional screening is required. Full article

(This article belongs to the Special Issue Molecular Research of Regulation of Red Blood Cells in Health, Hereditary or Acquired Diseases)

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13 pages, 328 KiB

Open AccessArticle

HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease

by Emmanuelle Bernit, Estelle Jean, Bastien Marlot, Laurine Laget, Caroline Izard, Isabelle Dettori, Sophie Beley, Isabelle Gautier, Imane Agouti, Coralie Frassati, Pascal Pedini, Christophe Picard, Julien Paganini, Jacques Chiaroni and Julie Di Cristofaro

Int. J. Mol. Sci. 2023, 24(17), 13591; https://doi.org/10.3390/ijms241713591 - 02 Sep 2023

Viewed by 1066

Abstract

Red blood cell (RBC) transfusion remains a critical component in caring for the acute and chronic complications of sickle cell disease (SCD). Patient alloimmunisation is the main limitation of transfusion, which can worsen anaemia and lead to delayed haemolytic transfusion reaction or transfusion deadlock. Although biological risk factors have been identified for immunisation, patient alloimmunisation remains difficult to predict. We aimed to characterise genetic alloimmunisation factors to optimise the management of blood products compatible with extended antigen matching to ensure the self-sufficiency of labile blood products. Considering alloimmunisation in other clinical settings, like pregnancy and transplantation, many studies have shown that HLA Ib molecules (HLA-G, -E, and -F) are involved in tolerance mechanism; these molecules are ligands of immune effector cell receptors (LILRB1, LILRB2, and KIR3DS1). Genetic polymorphisms of these ligands and receptors have been linked to their expression levels and their influence on inflammatory and immune response modulation. Our hypothesis was that polymorphisms of HLA Ib genes and of their receptors are associated with alloimmunisation susceptibility in SCD patients. The alloimmunisation profile of thirty-seven adult SCD patients was analysed according to these genetic polymorphisms and transfusion history. Our results suggest that the alloimmunisation of SCD patients is linked to both HLA-F and LILRB1 genetic polymorphisms located in their regulatory region and associated with their protein expression level. Full article

(This article belongs to the Special Issue Molecular Research of Regulation of Red Blood Cells in Health, Hereditary or Acquired Diseases)

11 pages, 1296 KiB

Open AccessArticle

Red Blood Cell Deformability Is Expressed by a Set of Interrelated Membrane Proteins

by Gregory Barshtein, Alexander Gural, Dan Arbell, Refael Barkan, Leonid Livshits, Ivana Pajic-Lijakovic and Saul Yedgar

Int. J. Mol. Sci. 2023, 24(16), 12755; https://doi.org/10.3390/ijms241612755 - 13 Aug 2023

Cited by 5 | Viewed by 1315

Abstract

Red blood cell (RBC) deformability, expressing their ability to change their shape, allows them to minimize their resistance to flow and optimize oxygen delivery to the tissues. RBC with reduced deformability may lead to increased vascular resistance, capillary occlusion, and impaired perfusion and oxygen delivery. A reduction in deformability, as occurs during RBC physiological aging and under blood storage, is implicated in the pathophysiology of diverse conditions with circulatory disorders and anemias. The change in RBC deformability is associated with metabolic and structural alterations, mostly uncharacterized. To bridge this gap, we analyzed the membrane protein levels, using mass spectroscopy, of RBC with varying deformability determined by image analysis. In total, 752 membrane proteins were identified. However, deformability was positively correlated with the level of only fourteen proteins, with a highly significant inter-correlation between them. These proteins are involved in membrane rafting and/or the membrane–cytoskeleton linkage. These findings suggest that the reduction of deformability is a programmed (not arbitrary) process of remodeling and shedding of membrane fragments, possibly mirroring the formation of extracellular vesicles. The highly significant inter-correlation between the deformability-expressing proteins infers that the cell deformability can be assessed by determining the level of a few, possibly one, of them. Full article

(This article belongs to the Special Issue Molecular Research of Regulation of Red Blood Cells in Health, Hereditary or Acquired Diseases)

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