DOCSLIB.ORG

Erythropoiesis Iron Metabolism: Interactions with Normal And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Erythropoiesis Iron Metabolism: Interactions with Normal And Downloaded from http://perspectivesinmedicine.cshlp.org/ on February 15, 2013 - Published by Cold Spring Harbor Laboratory Press Iron Metabolism: Interactions with Normal and Disordered Erythropoiesis Tomas Ganz and Elizabeta Nemeth Cold Spring Harb Perspect Med 2012; doi: 10.1101/cshperspect.a011668 Subject Collection Hemoglobin and Its Diseases Hemoglobin Variants: Biochemical Properties and The Prevention of Thalassemia Clinical Correlates Antonio Cao and Yuet Wai Kan Christopher S. Thom, Claire F. Dickson, David A. Gell, et al. Classification of the Disorders of Hemoglobin The Switch from Fetal to Adult Hemoglobin Bernard G. Forget and H. Franklin Bunn Vijay G. Sankaran and Stuart H. Orkin The Molecular Basis of α-Thalassemia Pathophysiology and Clinical Manifestations of Douglas R. Higgs the β-Thalassemias Arthur W. Nienhuis and David G. Nathan Evolution of Hemoglobin and Its Genes Development of Gene Therapy for Thalassemia Ross C. Hardison Arthur W. Nienhuis and Derek A. Persons The Search for Genetic Modifiers of Disease α-Thalassemia, Mental Retardation, and Severity in the β-Hemoglobinopathies Myelodysplastic Syndrome Guillaume Lettre Richard J. Gibbons World Distribution, Population Genetics, and β-Thalassemia Intermedia: A Clinical Perspective Health Burden of the Hemoglobinopathies Khaled M. Musallam, Ali T. Taher and Eliezer A. Thomas N. Williams and David J. Weatherall Rachmilewitz Iron Metabolism: Interactions with Normal and Hematopoietic Stem Cell Transplantation in Disordered Erythropoiesis Thalassemia and Sickle Cell Anemia Tomas Ganz and Elizabeta Nemeth Guido Lucarelli, Antonella Isgrò, Pietro Sodani, et al. Pluripotent Stem Cells in Research and Treatment of Hemoglobinopathies Natasha Arora and George Q. Daley For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/ Copyright © 2012 Cold Spring Harbor Laboratory Press; all rights reserved Downloaded from http://perspectivesinmedicine.cshlp.org/ on February 15, 2013 - Published by Cold Spring Harbor Laboratory Press Iron Metabolism: Interactions with Normal and Disordered Erythropoiesis Tomas Ganz and Elizabeta Nemeth Department of Medicine and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095 Correspondence: [email protected] Hemoglobinopathies and other disorders of erythroid cells are often associated with abnor- mal iron homeostasis. We review the molecular physiology of intracellular and systemic iron regulation, and the interactions between erythropoiesis and iron homeostasis. Finally, we discuss iron disorders that affect erythropoiesis as well as erythroid disorders that cause iron dysregulation. ron overload is a common complication of this environment, biological organisms evolved Ihemoglobinopathies treated by erythrocyte to conserve iron. Quantitative analysis of tissue transfusions (1 mL of packed erythrocytes con- iron distribution and fluxes in humans illus- tains about 1 mg of iron) and those associated trates how this is accomplished (Finch 1994). with ineffective erythropoiesis, which stimulates The typical adult human male contains about the hyperabsorption of dietary iron. With the 4 g of iron of which about 2.5 g is in hemoglo- increasing use of transfusion therapy, iron over- bin, 1 g is stored predominantly in hepatocytes load has become a major cause of morbidity and and hepatic and splenic macrophages, and most premature mortality. More recently, the effective of the rest is distributed in myoglobin, cyto- treatment of iron overload by iron chelation has chromes, and other ferroproteins. Only about dramatically improved survival (Cunningham 1–2 mg/d, or ,0.05%/d, is lost from the body 2008; Telfer2009). This work reviews recent ad- predominantly through desquamation and mi- vances in our understanding of the molecular nor blood loss. In the steady state, this amount www.perspectivesinmedicine.org basis of iron homeostasis and its disorders. is replaced through intestinal iron absorption. Although the loss of iron may increase slightly with increasing iron stores, these changes do not IRON BIOLOGY AND HOMEOSTASIS significantly contribute to homeostasis; intesti- nal iron absorption is by far the predominant Iron Intake determinant of the iron content of the body. A Iron is the most abundant element on Earth by typical Western diet provides about 15 mg of mass and the fourth most abundant in the iron per day and only 10% is absorbed. Re- Earth’s crust but it readily oxidizes into insolu- covery from blood loss causes an increase in iron ble compounds with poor bioavailability. In absorption up to 20-fold, indicating that the Editors: David Weatherall, Alan N. Schechter, and David G. Nathan Additional Perspectives on Hemoglobin and Its Diseases available at www.perspectivesinmedicine.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011668 Cite this article as Cold Spring Harb Perspect Med 2012;2:a011668 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on February 15, 2013 - Published by Cold Spring Harbor Laboratory Press T. Ganz and E. Nemeth duodenum where iron absorption takes place so this compartment must turn over every few has a large reserve capacity for iron absorption. hours. Erythrocyte precursors take up iron al- Pathological increase of intestinal iron absorp- most exclusively through transferrin receptors tion is a common cause of iron overload, ac- (TfR1) so the iron supply to erythrocyte precur- counting for the excess iron in hereditary hemo- sors is completely dependent on plasma trans- chromatosis and untransfused b-thalassemia. ferrin. In contrast, hepatocytes and other non- Blood transfusions and parenteral administra- erythroid cells can also take up iron that is not tion of iron compounds bypass the regulatory bound to transferrin (nontransferrin-bound bottleneck of iron absorption and constitute iron or NTBI), a process that becomes impor- the other major cause of iron overload. tant during iron overload when plasma trans- ferrin saturation reaches 100% (Breuer et al. 2000). The predominant cellular storage form Iron Recycling of iron is the hollow spherical protein ferritin Under normal circumstances, the reutilization whose cavity contains iron in ferric form com- of iron recycled from senescent cells accounts plexed with hydroxide and phosphate anions. for most of the iron flux in humans. With the erythrocyte lifespan of 120 d, 20–25 mg of iron Regulation of Plasma Iron Concentrations is required to replace the 20–25 mL of erythro- cytes that must be produced every day to main- Despite varying dietary iron intake and changes tain a steady state. Other cell types also turn over in erythropoietic activity owing to occasional but their much lower iron content contributes or periodic blood loss, iron concentrations in relatively little to the iron flux. Macrophages in plasma normally remain in the 10–30 mM range. the liver, spleen, and marrow (formerly called Chronically low concentrations decrease iron the reticuloendothelial system) phagocytose se- supply to erythropoiesis and other processes nescent or damaged erythrocytes, degrade their leading to anemia and dysfunction of other hemoglobin to release heme, extract iron from cell types sensitive to iron deprivation. Chroni- heme using heme oxygenase (Poss and Tonega- cally high iron concentrations lead to intermit- wa 1997), and recycle the iron to the extracellu- tent or steady-state saturation of transferrinwith lar fluid and plasma. Steady-state iron flux from iron and the generation of NTBI with conse- recycling can increase up to 150 mg/d in con- quent deposition of excess iron in the liver, en- ditions with ineffective erythropoiesis in which docrine glands, cardiac myocytes, and other tis- the number of erythroid precursors is increased sues. Excess cellular iron may cause tissue injury and accompanied by the apoptosis of hemoglo- by catalyzing the generation of reactive oxygen www.perspectivesinmedicine.org binized erythrocyte precursors in the marrow species, which can cause DNA damage, lipid and shortened erythrocyte survival (Beguin peroxidation, and oxidation of proteins. et al. 1988). Systemic Iron Homeostasis Iron Distribution and Storage Phenomenological description of systemic iron Free iron is highly reactive and causes cell and homeostasis was developed starting in the 1930s tissue injury through its ability to catalyze the (Finch 1994). Homeostatic mechanisms regu- production of reactive oxygen species. In living late dietary iron absorption and iron deposition organisms, iron is complexed with proteins or into or withdrawal from stores depending on the small organic molecules (citrate, acetate), which amount of stored iron (“stores regulator”) and mitigate its reactivity. Transferrin is the physio- the requirements of erythropoiesis (“erythro- logical carrier of iron in plasma. Normally, only poietic regulator”). The description of the mo- 20%–40% of the available binding sites on lecular processes that underlie iron homeostasis transferrin molecules are occupied by ferric has progressed rapidly in the last two decades iron. The iron content of plasma is only 2–3 mg but is still not complete. 2 Cite this article as Cold Spring Harb Perspect Med 2012;2:a011668 Downloaded from http://perspectivesinmedicine.cshlp.org/ on February 15, 2013 - Published by Cold Spring Harbor Laboratory Press Iron Metabolism CELLULAR IRON REGULATION ferrin-TfR1
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]
  • 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]
  • 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]
  • 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]
  • WBC Aplasia: Case Report
    Hematology & Transfusion International Journal Case Report Open Access WBC Aplasia: Case Report Abstract Volume 8 Issue 6 - 2020 Pure white cell aplasia (PWCA) is a rare acquired cause of agranulocytosis characterized Mariam AlGhazal,1 Rehab Bu Khamseen,1 by absence of all myeloid lineages in bone marrow with intact erythropoiesis and 2 2 megakaryopoiesis. Reported cases were associated with autoimmune conditions, thymomas, Mona AlZaher, Lama AlGharyafi, Zainab 2 1 chronic lymphocytic leukemia, infections, and as an adverse drug reaction. Presentation Alruwaiy, Manal alghazal 1 ranges from asymptomatic severe neutropenia to fatal sepsis. Several medications were Department of hematopathology Ministry of health, Dammam tried along with treatment of the underlying cause if identified. Steroids, immunoglobulin, regional laboratory & blood banking, Saudi Arabia 2 azathioprine, cyclosporine, rutiximab, GCSF and bone marrow transplant were all tried Department of hematology Dammam medical complex hospital, Saudi Arabia with variable response. Here we report a case of PWCA in middle age male, who responded to cyclosporine. Correspondence: Mariam AlGhazal, Department of hematopathology Ministry of health, Dammam regional laboratory & blood banking, Saudi Arabia, Email Received: November 12, 2020 | Published: November 26, 2020 Introduction of the total hematopoiesis and basically normoblastic in maturation. Megakaryocytes are present & normal in morphology Mature Pure white cell aplasia (PWCA) is a rare cause of neutropenia lymphocytes and plasma cells constitutes 50% and 2% respectively and mechanisms remain uncertain. The diagnosis is based on bone (there is around 11% large granular lymphocytes with abundant marrow examination, which reveals virtually absent granulopoiesis, cytoplasm & fine azurophilic granules out of total lymphocytes). 1 while erythropoiesis and megakaryocytopoiesis are intact.
    [Show full text]
  • Proposed Decision Memo for Erythropoiesis Stimulating Agents (Esas) for Non-Renal Disease Indications (CAG-00383N)
    Proposed Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N) Decision Summary Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, reduced survival) have prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). The initial scope of this national coverage analysis (NCA) was "non-renal" uses. Current non-renal indications for ESA use that are approved by the FDA are: cancer treatment related anemia (erythropoietin, darbepoetin), AZT-induced anemia in HIV-AIDS (erythropoietin only), and prophylactic use for select patients undergoing elective orthopedic procedures with significant expected blood loss (erythropoietin only) (Aranesp® drug label; Procrit® drug label). Because there is a preponderance of emerging data for ESA use in the oncology setting, the focus of the NCA will be ESA use in cancer and related conditions. The other non-renal uses may be addressed in future NCAs. We expect that our future reviews will also include the more adequately powered study of ESA use in spine surgery patients. In the interim, local Medicare contractors may continue to make reasonable and necessary determinations on all non-cancer and non-neoplastic conditions as well as other non-renal uses of ESAs. CMS is seeking public comment on our proposed determination that there is sufficient evidence to conclude that erythropoiesis stimulating agent (ESA) treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include: 1.
    [Show full text]
  • A Three-Dimensional in Vitro Model of Erythropoiesis Recapitulates Erythroid Failure in Myelodysplastic Syndromes
    Leukemia (2020) 34:271–282 https://doi.org/10.1038/s41375-019-0532-7 ARTICLE Myelodysplastic syndrome A three-dimensional in vitro model of erythropoiesis recapitulates erythroid failure in myelodysplastic syndromes 1 1 1 1 Edda María Elvarsdóttir ● Teresa Mortera-Blanco ● Marios Dimitriou ● Thibault Bouderlique ● 1 1 1 1 2 1 Monika Jansson ● Isabel Juliana F. Hofman ● Simona Conte ● Mohsen Karimi ● Birgitta Sander ● Iyadh Douagi ● 1 1 Petter S. Woll ● Eva Hellström-Lindberg Received: 19 January 2019 / Revised: 13 May 2019 / Accepted: 20 May 2019 / Published online: 2 August 2019 © The Author(s) 2019. This article is published with open access Abstract Established cell culture systems have failed to accurately recapitulate key features of terminal erythroid maturation, hampering our ability to in vitro model and treat diseases with impaired erythropoiesis such as myelodysplastic syndromes with ring sideroblasts (MDS-RS). We developed an efficient and robust three-dimensional (3D) scaffold culture model supporting terminal erythroid differentiation from both mononuclear (MNC) or CD34+-enriched primary bone marrow cells from healthy donors and MDS-RS patients. While CD34+ cells did not proliferate beyond two weeks in 2D suspension + 1234567890();,: 1234567890();,: cultures, the 3D scaffolds supported CD34 and MNC erythroid proliferation over four weeks demonstrating the importance of the 3D environment. CD34+ cells cultured in 3D facilitated the highest expansion and maturation of erythroid cells, including generation of erythroblastic islands and enucleated erythrocytes, while MNCs supported multi-lineage hemopoietic differentiation and cytokine secretion relevant for MDS-RS. Importantly, MDS-RS 3D-cultures supported de novo generation of ring sideroblasts and maintenance of the mutated clone.
    [Show full text]
  • Stress Erythropoiesis Is a Key Inflammatory Response
    cells Review Stress Erythropoiesis is a Key Inflammatory Response 1, 2 3, 3 Robert F. Paulson *, Baiye Ruan , Siyang Hao y and Yuanting Chen 1 Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease at Penn State University, University Park, PA 16802, USA 2 Department of Veterinary and Biomedical Sciences, Pathobiology Graduate Program at Penn State University, University Park, PA 16802, USA; [email protected] 3 Department of Veterinary and Biomedical Sciences, Graduate Program in Molecular, Cellular and Integrative Biosciences at Penn State University, University Park, PA 16802, USA; [email protected] (S.H.); [email protected] (Y.C.) * Correspondence: [email protected]; Tel.: +814-863-6306 Present Address: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, y USA; [email protected]. Received: 9 February 2020; Accepted: 3 March 2020; Published: 6 March 2020 Abstract: Bone marrow medullary erythropoiesis is primarily homeostatic. It produces new erythrocytes at a constant rate, which is balanced by the turnover of senescent erythrocytes by macrophages in the spleen. Despite the enormous capacity of the bone marrow to produce erythrocytes, there are times when it is unable to keep pace with erythroid demand. At these times stress erythropoiesis predominates. Stress erythropoiesis generates a large bolus of new erythrocytes to maintain homeostasis until steady state erythropoiesis can resume. In this review, we outline the mechanistic differences between stress erythropoiesis and steady state erythropoiesis and show that their responses to inflammation are complementary. We propose a new hypothesis that stress erythropoiesis is induced by inflammation and plays a key role in maintaining erythroid homeostasis during inflammatory responses.
    [Show full text]
  • Erythropoiesis and Splenomegaly
    Innate Immune Activation during Salmonella Infection Initiates Extramedullary Erythropoiesis and Splenomegaly This information is current as Amy Jackson, Minelva R. Nanton, Hope O'Donnell, Adovi of September 27, 2021. D. Akue and Stephen J. McSorley J Immunol published online 15 October 2010 http://www.jimmunol.org/content/early/2010/10/15/jimmun ol.1001198 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on September 27, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 15, 2010, doi:10.4049/jimmunol.1001198 The Journal of Immunology Innate Immune Activation during Salmonella Infection Initiates Extramedullary Erythropoiesis and Splenomegaly Amy Jackson, Minelva R. Nanton, Hope O’Donnell, Adovi D. Akue, and Stephen J. McSorley Systemic Salmonella infection commonly induces prolonged splenomegaly in murine or human hosts. Although this increase in splenic cellularity is often assumed to be due to the recruitment and expansion of leukocytes, the actual cause of splenomegaly remains unclear. We monitored spleen cell populations during Salmonella infection and found that the most prominent increase is found in the erythroid compartment.
    [Show full text]
  • Erythropoiesis Stimulating Agents (ESA)
    Erythropoiesis Stimulating Agents (ESA) Policy Number: Original Effective Date: MM.04.008 04/15/2007 Line(s) of Business: Current Effective Date: HMO; PPO; QUEST 03/01/2013 Section: Prescription Drugs Place(s) of Service: Home; Office; Outpatient I. Description Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor that regulates hemoglobin levels in response to changes in the blood oxygen concentration. Erythropoiesis- stimulating agents (ESAs) are produced using recombinant DNA technologies and have pharmacologic properties similar to EPO. The primary clinical use of ESAs is in patients with chronic anemia. II. Criteria/Guidelines A. Epoetin alfa and darbepoetin alfa are covered (subject to Limitations/Exclusions and Administrative Guidelines) for the following: 1. Treatment of anemia associated with chronic kidney disease, (pre-treatment hemoglobin is less than 10g/dL.) with or without the use of dialysis until hemoglobin reaches a target of 10 to 11 g/dL. 2. Treatment of anemia (pre-treatment hemoglobin is less than (10g/dL) in AZT-treated HIV infected patients, when the dose of AZT is equal to or less than 4,200 mg per week and the patient's pre-treatment endogenous erythropoietin level is less than or equal to 500 mUnits/mL. The maximum dosage of erythropoietin should not exceed a total of 60,000 units per week. 3. Treatment of anemia due to the effects of concomitantly administered chemotherapy in patients with non-myeloid malignancies. 4. Treatment of anemia (pre-treatment hemoglobin is greater than 10 to less than or equal to 13 g/dL) in patients scheduled to undergo elective, non-cardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.
    [Show full text]