DOCSLIB.ORG

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development cancers Review Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development Tomasz M. Grzywa 1,2,3 , Magdalena Justyniarska 1, Dominika Nowis 3,* and Jakub Golab 1,* 1 Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; [email protected] (T.M.G.); [email protected] (M.J.) 2 Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland 3 Laboratory of Experimental Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland * Correspondence: [email protected] (D.N.); [email protected] (J.G.) Simple Summary: Tumor immune evasion is one of the hallmarks of tumor progression that enables tumor growth despite the activity of the host immune system. It is mediated by various types of cells. Recently, immature red blood cells called erythroid progenitor cells (EPCs) were identified as regulators of the immune response in cancer. EPCs expand in cancer as a result of dysregulated erythropoiesis and potently suppress the immune response. Thus, targeting dysregulated EPC differentiation appears to be a promising therapeutic strategy. Abstract: Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), Citation: Grzywa, T.M.; Justyniarska, erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and M.; Nowis, D.; Golab, J. Tumor tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red Immune Evasion Induced by blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. Dysregulation of Erythroid EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), Progenitor Cells Development. interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress Cancers 2021, 13, 870. https:// T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune doi.org/10.3390/cancers13040870 suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to Academic Editor: Alberto Anel the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting Received: 20 January 2021 ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce Accepted: 15 February 2021 cancer-induced immunosuppression and the tumor-promoting effects of EPCs. Published: 19 February 2021 Keywords: immune evasion; erythroid progenitor cells; CD71+ erythroid cells; erythropoiesis; Publisher’s Note: MDPI stays neutral anemia; Ter-cells; ineffective erythropoiesis with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Cancer immunotherapy has strongly changed the therapeutic landscape in clinical oncology, leading to significant improvements in cancer patients survival [1]. However, de- Copyright: © 2021 by the authors. spite the induction of durable responses in an unprecedented percentage of cancer patients, Licensee MDPI, Basel, Switzerland. the majority still do not respond to the treatment and eventually progress to refractory This article is an open access article disease. There are several defined causes of immunotherapy resistance, including low distributed under the terms and tumor mutational burden [2], impaired antigen presentation by the major histocompatibil- conditions of the Creative Commons ity complex (MHC) proteins [3], loss of interferon-γ (IFN-γ) and tumor necrosis factor-α Attribution (CC BY) license (https:// (TNF-α) pathway genes [4,5], as well as the development of immunosuppressive tumor creativecommons.org/licenses/by/ microenvironment (TME) [6,7]. 4.0/). Cancers 2021, 13, 870. https://doi.org/10.3390/cancers13040870 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 870 2 of 33 TME is composed of many types of cells that regulate tumor growth and progression [8]. The role of regulatory T-cells (Tregs) [9], myeloid-derived suppressor cells (MDSCs) [10], tumor-associated macrophages (TAMs) [11], tumor-associated neutrophils (TANs) [12], and cancer-associated fibroblasts (CAFs) [13] in the regulation of anti-tumor immune response has been established by many years of research (Table1). Recent reports point to another population of cells, i.e., erythroid progenitor cells (EPCs), that regulate local and systemic immunity in cancer. These cells use similar mechanisms to immune cells and are crucial in the regulation of immune response and cancer progression. Table 1. Immunomodulatory cells in cancer and their mechanisms of immune regulation. Cells Mechanisms Effects Ref IL-10 T-cell suppression [14] Regulatory T-cells IL-2 consumption T-cell suppression [15] (Tregs) COX-2 and PGE2 T-cell suppression [16] Adenosine T-cell suppression [17] ARG1 T-cell suppression [18] T-cell suppression IDO Tregs induction [19,20] NK cell suppression PD-L1/PD-1 T-cell suppression [21] Myeloid-derived IL-10 Tregs induction [22] suppressor cells TGF-β Tregs induction [22] (MDSCs) CD40/CD40L Tregs activation [23] Depletion of cystine and cysteine T-cell suppression [24] ROS T-cell suppression [25] Resistance to Free radical peroxynitrite [26] cytotoxic T-cells Decreased PD-L1/PD-1 [27] phagocytosis ARG1 T-cell suppression [28] IL-10 T-cell suppression [29] Tumor associated MDSC infiltration macrophages (TAMs) IL-1β Induction of the [30,31] protumor phenotype Induction of T-cell IL-12 [32] response Induction of TNF-α [33] anti-tumor response ARG1 T-cell suppression [18,28] Tumor associated T-cell suppression NOS [34,35] neutrophils (TANs) T-cell apoptosis PD-L1/PD-1 T-cell suppression [36] PD-L1/PD-1 T-cell suppression [37] FasL, PD-L2 T-cell suppression [38] Cancer associated Induction of PD-L1+ fibroblasts (CAFs) IL-6 [39] TANs Chemokines MDSC infiltration [40] ROS T-cell suppression [41,42] Erythroid progenitor IL-10 T-cell suppression [42] cells (EPCs) PD-L1/PD-1 T-cell suppression [43] TGF-β T-cell suppression [42] ARG1—arginase 1, COX-2—cyclooxygenase-2, FasL—Fas ligand (CD95L, CD178), IDO—Indoleamine-pyrrole 2,3-dioxygenase, IL—interleukin, NK—natural killer, NOS—nitric oxide synthase, PD-1—programmed cell death 1, PD-L1—programmed death-ligand 1, PGE2—Prostaglandin E2, ROS—reactive oxygen species, TGF-β—transforming growth factor β, TNF-α—tumor necrosis factor α. Cancers 2021, 13, 870 3 of 33 In this review, we discuss the role of the dysregulation of erythropoiesis by cancer cells to induce immune evasion and promote cancer progression. 2. Regulation of Erythropoiesis The differentiation of hematopoietic stem cells (HSCs) to erythroid cells is a stepwise process strictly regulated by multiple intrinsic and extrinsic factors (Table2), which results in the production of over 2 × 1011 red blood cells (RBCs) per day and allows for the maintenance of erythroid homeostasis [44–48]. This complex net of interactions provides adequate production of RBCs depending on the body’s needs. Insufficient oxygen supply to the peripheral tissues resulting in hypoxia is a key trigger of increased erythropoiesis, which is regulated by the increased production of erythropoietin (EPO) in the kidney peritubular fibroblasts and liver interstitial cells and hepatocytes [49]. Table 2. Regulation of erythropoiesis. Factor Role in Erythropoiesis Dysregulation in Cancer References SCF Growth factors regulating Production in TME [50,51] G-CSF early stages of Increased serum [52] IL-3 erythropoiesis concentration [53] Increased serum EPO [54] Growth factors regulating concentration GDF11late stages of erythropoiesis Production in TME [55] Activin A Production in TME [56] Decreased expression in GATA1 Crucial TFs regulating [57–59] EPCs in cancer erythropoiesis Increased in EPCs in MPNs STAT5 Decreased in EPCs in [60,61] iron deficiency MCL-1 Survival factors for BCL-xL erythroid cells HSP70 Production in TME TGF-β [62] Increased concentration Increased level in EPCs SMAD signaling Negative regulators [62] in cancer of erythropoiesis High expression on FasL [59,63] cancer cells Increased level in EPCs Fas [59,63] in cancer Decreased in a subset Vitamin B12 [64] of patients Decreased in a subset Folic Acid [64] of patients CopperEssential vitamins, trace Increased concentration [65] elements, and Decreased in a subset Iron [66] iron-metabolism proteins of patients Ferritin Decreased or increased [66] Decreased in a subset Transferrin [66] of patients Ferroportin Decreased expression [67] Hepcidin Increased concentration [68] MPN—myeloproliferative neoplasm, TF—transcription factor, TME—tumor microenvironment. HSCs reside in a unique niche that is created and regulated by various cell types, growth factors, and chemokines [69]. The commitment of HSCs to erythroid lineage begins with the differentiation to a multipotent megakaryocyte–erythroid progenitor cell (MEP), followed by a bust-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid Cancers 2021, 13, 870 4 of 33 (CFU-E). During terminal erythropoiesis, CFU-E differentiates into proerythroblasts,
Load more

Recommended publications
  • Mechanisms of Erythrocyte Development and Regeneration: Implications for Regenerative Medicine and Beyond Emery H
    © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev151423. http://dx.doi.org/10.1242/dev.151423 REVIEW Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond Emery H. Bresnick1,*, Kyle J. Hewitt1, Charu Mehta1, Sunduz Keles2, Robert F. Paulson3 and Kirby D. Johnson1 ABSTRACT better understanding of how stress can influence erythropoiesis, Hemoglobin-expressing erythrocytes (red blood cells) act as both during development and in a regenerative context. In this fundamental metabolic regulators by providing oxygen to cells and Review, we focus on cell-autonomous and non-cell-autonomous tissues throughout the body. Whereas the vital requirement for mechanisms governing erythrocyte development, the applicability oxygen to support metabolically active cells and tissues is well of these mechanisms to stress-instigated erythropoiesis (erythrocyte established, almost nothing is known regarding how erythrocyte regeneration) and their implications for other regenerative development and function impact regeneration. Furthermore, many processes. We begin by considering the principles that govern the questions remain unanswered relating to how insults to hematopoietic cell fate transitions that produce the diverse complement of blood stem/progenitor cells and erythrocytes can trigger a massive cells, including erythrocytes. It is not our intent, however, to regenerative process termed ‘stress erythropoiesis’ to produce comprehensively address this topic, as it has been heavily reviewed billions of erythrocytes. Here, we review the cellular and molecular elsewhere (Crisan and Dzierzak, 2016; Dzierzak and de Pater, 2016; mechanisms governing erythrocyte development and regeneration, Orkin and Zon, 2008; Tober et al., 2016). and discuss the potential links between these events and other regenerative processes.
    [Show full text]
  • Fetal-Like Erythropoiesis During Recovery from Transient Erythroblastopenia of Childhood (TEC)
    Pediatr. Res. 15: 1036-1039 (198 1) erythrocyte, aplasia transient erythroblastopenia of childhood fetal-like erythropoiesis Fetal-Like Erythropoiesis during Recovery from Transient Erythroblastopenia of Childhood (TEC) Division of Hematolog). and Oncology, Children's Hospital Medical Center and the Sidney Farber Cancer It~stitule, and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA Summary bone marrow failure (7.%. 16)' or in states of ra~idbone marrow recovery from aplasia after bone marrow transplantation (1, 3, Fetal-like erythropoiesis frequently accompanies marrow stress 17). The term "fetal-like" is used because the erythrocytes may conditions such as Diamond-Blackfan syndrome and aplastic ane- express only one and not all of the characteristics of fetal red mia. In contrast, patients with transient erythroblastopenia of blood cells. childhood have erythrocytes which lack fetal characteristics at the To if fetal-like erythropoiesis accompanies bone mar- time of diagnosis. This report describes nine children with transient row recovery from other hypoplastic states, we studied children erythroblastopenia of childhood in whom transient, fetal-like eryth- with transient erythroblastopenia of childhood (TEC) from the was observed during the period These pa- tirne of presentation to full recovery, TEC is an unusual disease of tients initially presented with anemia, reticulocytopenia, erythro- infants and young children, characterized by the insidious onset cytes of normal size for age, low levels of fetal hemoglobin, and of hypoproliferative anemia without decreases in leukocyte and i-antigen. During the recovery period, however, erythrocytes man- platelet production. Although the anemia may be quite severe at ifested one or more fetal characteristics. These included an in- presentation, rapid and complete recovery is the rule with per- creased fetal hemoglobin (in three of five patients), the presence manent restoration of normal hematopoiesis (2, 11, 19, 23, 25, 26).
    [Show full text]
  • The Role of Macrophages in Erythropoiesis and Erythrophagocytosis
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Frontiers - Publisher Connector REVIEW published: 02 February 2017 doi: 10.3389/fimmu.2017.00073 From the Cradle to the Grave: The Role of Macrophages in Erythropoiesis and Erythrophagocytosis Thomas R. L. Klei†, Sanne M. Meinderts†, Timo K. van den Berg and Robin van Bruggen* Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands Erythropoiesis is a highly regulated process where sequential events ensure the proper differentiation of hematopoietic stem cells into, ultimately, red blood cells (RBCs). Macrophages in the bone marrow play an important role in hematopoiesis by providing signals that induce differentiation and proliferation of the earliest committed erythroid progenitors. Subsequent differentiation toward the erythroblast stage is accompanied by the formation of so-called erythroblastic islands where a central macrophage provides further cues to induce erythroblast differentiation, expansion, and hemoglobinization. Edited by: Robert F. Paulson, Finally, erythroblasts extrude their nuclei that are phagocytosed by macrophages Pennsylvania State University, USA whereas the reticulocytes are released into the circulation. While in circulation, RBCs Reviewed by: slowly accumulate damage that is repaired by macrophages of the spleen. Finally, after Xinjian Chen, 120 days of circulation, senescent RBCs are removed from the circulation by splenic and University of Utah, USA Reinhard Obst, liver macrophages. Macrophages are thus important for RBCs throughout their lifespan. Ludwig Maximilian University of Finally, in a range of diseases, the delicate interplay between macrophages and both Munich, Germany developing and mature RBCs is disturbed. Here, we review the current knowledge on *Correspondence: Robin van Bruggen the contribution of macrophages to erythropoiesis and erythrophagocytosis in health [email protected] and disease.
    [Show full text]
  • Erythroid Lineage Cells in the Liver: Novel Immune Regulators and Beyond
    Review Article Erythroid Lineage Cells in the Liver: Novel Immune Regulators and Beyond Li Yang*1 and Kyle Lewis2 1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2Division of Gastroenterology, Hepatology & Nutrition Developmental Biology Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Abstract evidenced by both in vivo and in vitro studies in mouse and human. In addition, we also shed some light on the emerging The lineage of the erythroid cell has been revisited in recent trends of erythroid cells in the fields of microbiome study and years. Instead of being classified as simply inert oxygen regenerative medicine. carriers, emerging evidence has shown that they are a tightly regulated in immune potent population with potential devel- Erythroid lineage cells: Natural history in the liver opmental plasticity for lineage crossing. Erythroid cells have been reported to exert immune regulatory function through Cellular markers for staging of erythroid cells secreted cytokines, or cell-cell contact, depending on the conditions of the microenvironment and disease models. In There are different stages during erythropoiesis. The cells of this review, we explain the natural history of erythroid cells in interest for this review, referred as “erythroid lineage cells” the liver through a developmental lens, as it offers perspec- or “CD71+ erythroid cells”, represent a mix of erythroblasts, tives into newly recognized roles of this lineage in liver including basophilic, polychromatic, and orthochromatic biology. Here, we review the known immune roles of erythroid erythroblasts. A widely used assay relies on the cell- cells and discuss the mechanisms in the context of disease surface markers CD71 and Ter119, and on the flow-cyto- models and stages.
    [Show full text]
  • Lecture 2 Haemopoiesis, Erythropoiesis and Leucopoiesis Haemopoiesis Haemopoiesis Or Haematopoiesis Is the of Process Formation of New Blood Cellular Components
    NPTEL – Biotechnology – Cell Biology Lecture 2 Haemopoiesis, erythropoiesis and leucopoiesis Haemopoiesis Haemopoiesis or haematopoiesis is the of process formation of new blood cellular components. It has been estimated that in an adult human, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation. The mother cells from which the progeny daughter blood cells are generated are known as haematopoietic stem cells. In an embryo yolk sac is the main site of haemopoiesis whereas in human the basic sites where haemopoiesis occurs are the bone marrow (femur and tibia in infants; pelvis, cranium, vertebrae, and sternum of adults), liver, spleen and lymph nodes (Table 1). In other vertebrates haemapoiesis occurs in loose stroma of connective tissue of the gut, spleen, kidney or ovaries. Table 1: Sites of Haemopoiesis in humans Stage Sites Fetus 0–2 months (yolk sac) 2–7 months (liver, spleen) 5–9 months (bone marrow) Infants Bone marrow Adults Vertebrae, ribs, sternum, skull, sacrum and pelvis, proximal ends of femur The process of haemopoiesis Pluripotent stem cells with the capability of self renewal, in the bone marrow known as the haemopoiesis mother cell give rise to the separate blood cell lineages. This haemopoietic stem cell is rare, perhaps 1 in every 20 million nucleated cells in bone marrow. Figure 1 illustrates the bone marrow pluripotent stem cell and the cell lines that arise from it. Cell differentiation occurs from a committed progenitor haemopoietic stem cell and one stem cell is capable of producing about 106 mature blood cells after 20 cell divisions.
    [Show full text]
  • Lesson-1 Composition of Blood and Normal Erythropoiesis
    Composition of Blood and Normal Erythropoiesis MODULE Hematology and Blood Bank Technique 1 COMPOSITION OF BLOOD AND Notes NORMAL ERYTHROPOIESIS 1.1 INTRODUCTION Blood consists of a fluid component- plasma, and a cellular component comprising of red cells, leucocytes and platelets, each of them with distinct morphology and a specific function. Erythrocytes or red cells are biconcave discs. They do not have a nucleus and are filled with hemoglobin which carries oxygen to tissues and carbon dioxide from the tissues to the lungs. Platelets are small cells. They also do not have a nucleus and are essential for clotting of blood. Leucocytes play an important role in fighting against infection. All these cells arise from a single cell called as the Hematopoietic stem cell. The process of formation of these cells is called Hematopoiesis. In this lesson we will learn the different stages in the development of red cells. The process of formation of red cells is called erythropoiesis. OBJECTIVES After reading this lesson, you will be able to: z explain the composition of blood z describe various stages in the formation of red cells z explain the precautions in handling blood and blood products z explain steps for preventing injury from sharp items. 1.2 SITES OF HEMATOPOIESIS It begins in the early prenatal period, within the first two weeks, in the yolk sac in the form of blood islands and is known as primitive hematopoiesis. The red cells formed at this time are nucleated and contain embryonic type of hemoglobin which differs in the type of globin chains from the adult hemoglobin.
    [Show full text]
  • Haematopoiesis to Describe the Components of Normal Blood, Their Relative Proportions and Their Functions
    Haematopoiesis To describe the components of normal blood, their relative proportions and their functions Blood 8% of body weight Plasma (55%) clear, 90% water, contains salts, enzymes, proteins WBCs and platelet (1%) RBCs (45%) bioconcave– disc, no nucleus = anuclear- 120days lifespan Immature = blasts– Mature= cytes In white blood cells myeloblast goes to neutrophils, basophils, eosinophils Monoblast= monocyte can also become dendritic cells and macrophages – White blood cells (leukocytes)– Polymorphonuclear= neutrophils, eosinophil s, basophils Mononuclear= lymphocytes= T cells, B cells and’ monocytes Lymphoid= NK cells, T-Lymphocyte, B-lymphocyte Myeloid= Monocyte, erythrocyte, neutrophils, basophils, eosinophils, mast cells, megakaryocyte, mast cells BOTH Dendritic cells (from monocyte in myeloid) (lymphoid precursor) Neutrophil – protection from bacteria and fungi Eosinophil- protection against parasites Basophil – increase during allergic reactions Lymphocytes – T cells- protection against viruses, B cells immunoglobulin synthesis Monocyte- protection from back bacteria and fungi phagocytosis – How do blood go from bone to blood vessels? – The bones are perfused with blood vessels- How do we investigate blood? In venepuncture, the superficial veins of the upper limbs are selected and hollow needle is inserted through the skin into the veins. Blood is then collected into evacuated tubes. These veins are present in numbers and are easily accessible. Anticoagulant, EDTA is used to stop blood clotting 1.Using Automated the sample full collected…. blood count Whole blood for a FBC is usually taken into an EDTA tube to stop it from clotting. The blood is well mixed and put through a machine called an automated analyser, counts the numbers and size of RBC and platelets within the blood using sensors Reticulocyte Assessing the young RBCs numbers performed by automated cell counters give indication of output of young RBC by bone marrow – 2.
    [Show full text]
  • Regulation of Erythropoiesis in the Fetus and Newborn
    Arch Dis Child: first published as 10.1136/adc.47.255.683 on 1 October 1972. Downloaded from Review Article Archives of Disease in Childhood, 1972, 47, 683. Regulation of Erythropoiesis in the Fetus and Newborn PER HAAVARDSHOLM FINNE and SVERRE HALVORSEN From the Paediatric Research Institute, Barneklinikken, Rikshospitalet, Oslo, Norway The present concept of the regulation of erythro- sis in the human is predominantly myeloid during poiesis is based on the theory that a humoral factor, normal conditions. In other species (mice, rats) erythropoietin, stimulates red cell production it is different, with the shift from hepatic to myeloid through its effects on the erythropoietin sensitive stage occurring after birth (Lucarelli, Howard, stem cell, on DNA synthesis in the erythroblast, and Stohlman, 1964; Stohlman, 1970). and on the release of reticulocytes (Gordon and A progressive increase in erythrocyte content per Zanjani, 1970; Hodgson, 1970). Erythropoietin ml and in Hb concentration has been found in production is regulated by the difference between human blood during the course of intrauterine oxygen supply and demand within the oxygen development, leading to the normal high values at sensitive cells in the kidney. As a response to birth (Thomas and Yoffey, 1962; Walker and hypoxia, a factor called erythrogenin is produced in Tumbull, 1953). Marks, Gairdner, and Roscoe the kidney. This factor acts on a serum substrate (1955), however, found no increase in Hb values copyright. to generate an active humoral factor, the erythro- with gestational age after 31 weeks gestation. poietic stimulating factor (ESF) or erythropoietin The alteration in Hb structure during intrauterine (Gordon, 1971), increased amount of which leads and early neonatal life changes its physical proper- to increased red cell production.
    [Show full text]
  • Bleeding Fevers! Thrombocytopenia and Neutropenia
    Bleeding fevers! Thrombocytopenia and neutropenia Faculty of Physician Associates 4th National CPD Conference Monday 21st October 2019, Royal College of Physicians, London @jasaunders90 | #FPAConf19 Jamie Saunders MSc PA-R Physician Associate in Haematology, Guy’s and St Thomas’ NHS Foundation Trust Board Member, Faculty of Physician Associates Bleeding fevers; Thrombocytopenia and neutropenia Disclosures / Conflicts of interest Nothing to declare Professional Affiliations Board Member, Faculty of Physician Associates Communication Committee, British Society for Haematology Education Committee, British Society for Haematology Bleeding fevers; Thrombocytopenia and neutropenia What’s going to be covered? - Thrombocytopenia (low platelets) - Neutropenia (low neutrophils) Bleeding fevers; Thrombocytopenia and neutropenia Thrombocytopenia Bleeding fevers; Thrombocytopenia (low platelets) Pluripotent Haematopoietic Stem Cell Myeloid Stem Cell Lymphoid Stem Cell A load of random cells Lymphoblast B-Cell Progenitor Natural Killer (NK) Precursor Megakaryoblast Proerythroblast Myeloblast T-Cell Progenitor Reticulocyte Megakaryocyte Promyelocyte Mature B-Cell Myelocyte NK-Cell Platelets Red blood cells T-Cell Metamyelocyte IgM Antibody Plasma Cell Secreting B-Cell Basophil Neutrophil Eosinophil IgE, IgG, IgA IgM antibodies antibodies Bleeding fevers; Thrombocytopenia (low platelets) Platelet physiology Mega Liver TPO (Thrombopoietin) TPO-receptor No negative feedback to liver Plt Bleeding fevers; Thrombocytopenia (low platelets) Platelet physiology
    [Show full text]
  • Nucleated Red Blood Cells
    Erythropoiesis Nucleated red blood cells Proerythroblast Physiology The red cell line develops from a pluripotent stem cell. With adults under physiological conditions, this development takes place exclusively in the bone marrow. Stimulated Glycophorin 103 by erythropoietin, the stem cells develop via Transferrin receptor progenitors, which are not identifiable using 102 MGG staining, into proerythroblasts, which are the first red blood cell precursors recog- 101 HLe-1 nizable by panoptic staining. Size A: mature red cell; B: reticulocyte; C: orthochromatic eryth- roblast; D: polychromatic erythroblast; E: basophilic eryth- roblast; F: proerythroblast; G: undifferentiated blast G F E D C B A Basophilic erythroblast Proerythroblast Blast-like cell. Size 14 – 18 μm. Nucleus-cytoplasm ratio (N:C ratio) 80 %. Chromatin slightly clumped with one or more prominent nucleoli, slightly more dense than that of a myeloblast. Cytoplasm dark blue, agranular, often with perinuclear halo, which repesents the Golgi apparatus. Erythroblast Smaller than the proerythroblasts. Nuclear chromatin heterogeneous with condensed or clumped DNA. Generally erythroblasts (E) are separated into three maturation stages. Similarities: decrease in cell and nucleus size, chromatin more and more unevenly distributed and darker stained. Differences: colour of the cytoplasm changing from blue (RNA) to red (haemoglobin). By this colour, erythroblasts are divided into basophilic E (blue), N:C ratio 70 – 80 %, polychromatic E (mixed colour: blue-grey/red), N:C ratio 30 – 50 %, and orthochromatic E (pink-orange), N:C ratio approx. 30 %. Orthochromatic erythroblasts are Polychromatic erythroblast Orthochromatic erythroblast the last maturation stage and the nucleus undergoes pyknotic degeneration. During the following four days RNA remnants are degraded.
    [Show full text]
  • Final Copy 2019 01 23 Hampton-O'neil L Phd
    This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Hampton-O'Neil, Lea Title: Investigating the formation of erythroblastic islands General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. INVESTIGATING THE FORMATION OF ERYTHROBLASTIC ISLANDS Lea Alice Hampton-O’Neil University of Bristol School of Biochemistry University Walk Bristol UK January 2019 A dissertation submitted to the University of Bristol in accordance with the requirements of the degree of Doctor of Philosophy in the Faculty of Biomedical Sciences Word count: 42 001 i Abstract Erythropoiesis is one of the most efficient cellular processes in the human body producing approximately 2.5 million red blood cells every second.
    [Show full text]
  • Resolving the Distinct Stages in Erythroid Differentiation Based on Dynamic Changes in Membrane Protein Expression During Erythropoiesis
    Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis Ke Chena,1, Jing Liua,1, Susanne Heckb, Joel A. Chasisc, Xiuli Ana,d,2, and Narla Mohandasa aRed Cell Physiology Laboratory, bFlow Cytometry Core, New York Blood Center, New York, NY 10065; cLife Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; and dDepartment of Biophysics, Peking University Health Science Center, Beijing 100191, China Communicated by Joseph F. Hoffman, Yale University School of Medicine, New Haven, CT, August 18, 2009 (received for review June 25, 2009) Erythropoiesis is the process by which nucleated erythroid progeni- results in loss of cohesion between the bilayer and the skeletal tors proliferate and differentiate to generate, every second, millions network, leading to membrane loss by vesiculation. This diminution of nonnucleated red cells with their unique discoid shape and mem- in surface area reduces red cell life span with consequent anemia. brane material properties. Here we examined the time course of A number of additional transmembrane proteins, including CD44 appearance of individual membrane protein components during and Lu, have been characterized, although their structural organi- murine erythropoiesis to throw new light on our understanding of zation in the membrane has not been fully defined. the evolution of the unique features of the red cell membrane. We Some transmembrane proteins exhibit multiple functions. Band found that the accumulation of all of the major transmembrane and 3 serves as an anion exchanger, while Rh/RhAG are probably gas all skeletal proteins of the mature red blood cell, except actin, accrued transporters (8, 9), and Duffy functions as a chemokine receptor progressively during terminal erythroid differentiation.
    [Show full text]