Macrophages Regulate Stress Erythropoiesis Through Direct Cellular Interactions Associated With Integrin β1-Focal Adhesion Kinase Signaling
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Ineffective erythropoiesis
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Growth differentiation factor 15 (GDF15) was identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. This review addresses the regulation, expression and potential functions of GDF15 in the context of erythroid biology.GDF15 expression during late erythroid differentiation was discovered as part of an erythroblast transcriptome project. As GDF15 expression is associated with cellular stress or apoptosis, further investigation of the cytokine was focused upon its involvement in ineffective erythropoiesis. Remarkably high serum levels were detected in patients with thalassemia syndromes, congenital dyserythropoiesis and some acquired sideroblastic anemias. High-level GDF15 expression is not a feature of normal erythropoiesis, or erythroid recovery after bone-marrow transplantation. As GDF15 is a transforming growth factor-beta superfamily member, it was investigated as an effector of ineffective erythropoiesis that suppresses hepcidin expression despite iron overloading.In contrast to the low levels of GDF15 expressed during normal erythropoiesis, ineffective erythropoiesis causes high-level expression of GDF15. In patients with thalassemia and related anemias, GDF15 expression may contribute to iron overloading or other features of the disease phenotype.
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Erythropoiesis is the process in which new erythrocytes are produced. These new erythrocytes replace the oldest erythrocytes (normally about one percent) that are phagocytosed and destroyed each day. Folate, vitamin B12, and iron have crucial roles in erythropoiesis. Erythroblasts require folate and vitamin B12 for proliferation during their differentiation. Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes erythroblast apoptosis, resulting in anemia from ineffective erythropoiesis. Erythroblasts require large amounts of iron for hemoglobin synthesis. Large amounts of iron are recycled daily with hemoglobin breakdown from destroyed old erythrocytes. Many recently identified proteins are involved in absorption, storage, and cellular export of nonheme iron and in erythroblast uptake and utilization of iron. Erythroblast heme levels regulate uptake of iron and globin synthesis such that iron deficiency causes anemia by retarded production rates with smaller, less hemoglobinized erythrocytes.
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Purpose of review In thalassemia, ineffective erythropoiesis is characterized by apoptosis of the maturing nucleated erythroid cells. New studies also suggest that limited erythroid cell differentiation plays a role in the development of ineffective erythropoiesis. This would further exacerbate anemia and increase iron absorption. Recent findings During erythroid differentiation and maturation, it is critical that the components of hemoglobin are made in stoichiometric amounts. It is, therefore, conceivable that factors that modify this process intrinsically or extrinsically will also affect erythropoiesis. Several proteins have the potential to alter erythroid replication and differentiation in conditions of ineffective erythropoiesis. Elevated erythropoietin levels increase the number of erythroid precursors bearing a phosphorylated form of Jak2. This, in a pathological condition, may contribute to limited erythroid differentiation. Unbalanced synthesis of globins and heme modifies the activity of the heme-regulated inhibitor kinase, affecting proliferation and differentiation of the erythroid precursors. In addition, inefficient elimination of reactive oxygen species, which are increased under conditions of iron overload, may also hamper erythropoiesis. Summary Use of Jak2 inhibitors may limit the overproduction of immature erythroid cells in thalassemia, with the potential of reversing extramedullary hematopoiesis and preventing splenectomy. In addition, preventing iron overload and formation of reactive oxygen species may also be beneficial in limiting tissue damage and ineffective erythropoiesis.
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Erythropoiesis is a complex process that starts in the course of embryo formation and it is maintained throughout the life of an organism. During the fetal development, erythropoiesis arises from different body sites and erythroblast maturation occurs in the fetal liver. After birth, erythropoiesis and erythroblast maturation take place exclusively in the bone marrow, generating a lifetime reservoir of red blood cells (RBCs), which are responsible for transporting oxygen through the bloodstream to tissues and organs. Several transcription factors and cytokines, such as GATA-1, GATA-2, FOG-1 and erythropoietin (EPO), constitute an elaborated molecular network that regulates erythropoiesis as they are involved in the differentiation and maturation of RBCs. The profound understanding of erythropoiesis is fundamental to avoid, treat or even soften the effects of erythropoietic clinical disorders and may be useful to improve patients' well-being.
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From rat bone marrow in which erythropoiesis has been depressed (by suppression of erythropoietin production), liquid culture has yielded a predominantly synchronous amplification of erythroblast development. Groups of 2, 4, 8, 16 and 32 erythrolbasts are observed at 9-15 hour intervals in successive stages of maturation, similar (by their staining characteristics and nuclear size) to that seen in vivo.
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Erythroblast
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Homeostasis
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Background Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis. Methodology/Principal Findings We used a transplant model to induce stress conditions. In irradiated recipients that received hmox+/− or hmox+/+ bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1+-cells expressing TNF-α. In the spleens of mice that received hmox+/− cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1+-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations. Conclusions/Significance As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.
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In humans, β -thalassemia dyserythropoiesis is characterized by expansion of early erythroid precursors and erythroid progenitors and then ineffective erythropoiesis. This ineffective erythropoiesis is defined as a suboptimal production of mature erythrocytes originating from a proliferating pool of immature erythroblasts. It is characterized by (1) accelerated erythroid differentiation, (2) maturation blockade at the polychromatophilic stage, and (3) death of erythroid precursors. Despite extensive knowledge of molecular defects causing β -thalassemia, less is known about the mechanisms responsible for ineffective erythropoiesis. In this paper, we will focus on the underlying mechanisms leading to premature death of thalassemic erythroid precursors in the bone marrow.
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