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Cold Spring Harbor Perspectives in... Apr 2013Through their oxygen delivery function, red blood cells are pivotal to the healthy existence of all vertebrate organisms. These cells are required during all stages of... (Review)
Review
Through their oxygen delivery function, red blood cells are pivotal to the healthy existence of all vertebrate organisms. These cells are required during all stages of life--embryonic, fetal, neonatal, adolescent, and adult. In the adult, red blood cells are the terminally differentiated end-product cells of a complex hierarchy of hematopoietic progenitors that become progressively restricted to the erythroid lineage. During this stepwise differentiation process, erythroid progenitors undergo enormous expansion, so as to fulfill the daily requirement of ~2 × 10(11) new erythrocytes. How the erythroid lineage is made has been a topic of intense research over the last decades. Developmental studies show that there are two types of red blood cells--embryonic and adult. They develop from distinct hemogenic/hematopoietic progenitors in different anatomical sites and show distinct genetic programs. This article highlights the developmental and differentiation events necessary in the production of hemoglobin-producing red blood cells.
Topics: Animals; Cell Differentiation; Embryonic Development; Erythrocytes; Erythropoiesis; Growth and Development; Hematopoietic Stem Cells; Humans; Transcription Factors
PubMed: 23545573
DOI: 10.1101/cshperspect.a011601 -
Annual Review of Immunology Apr 2023Maintaining the correct number of healthy red blood cells (RBCs) is critical for proper oxygenation of tissues throughout the body. Therefore, RBC homeostasis is a... (Review)
Review
Maintaining the correct number of healthy red blood cells (RBCs) is critical for proper oxygenation of tissues throughout the body. Therefore, RBC homeostasis is a tightly controlled balance between RBC production and RBC clearance, through the processes of erythropoiesis and macrophage hemophagocytosis, respectively. However, during the inflammation associated with infectious, autoimmune, or inflammatory diseases this homeostatic process is often dysregulated, leading to acute or chronic anemia. In each disease setting, multiple mechanisms typically contribute to the development of inflammatory anemia, impinging on both sides of the RBC production and RBC clearance equation. These mechanisms include both direct and indirect effects of inflammatory cytokines and innate sensing. Here, we focus on common innate and adaptive immune mechanisms that contribute to inflammatory anemias using examples from several diseases, including hemophagocytic lymphohistiocytosis/macrophage activation syndrome, severe malarial anemia during infection, and systemic lupus erythematosus, among others.
Topics: Humans; Animals; Anemia; Erythropoiesis; Erythrocytes; Malaria; Macrophages
PubMed: 36750316
DOI: 10.1146/annurev-immunol-101320-125839 -
Molecular Medicine Reports Feb 2019The purpose of this review is to summarize the research progress of PI3K/Akt signaling pathway in erythropoiesis and glycolysis.... (Review)
Review
The purpose of this review is to summarize the research progress of PI3K/Akt signaling pathway in erythropoiesis and glycolysis. Phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K) is activated by numerous genes and leads to protein kinase B (Akt) binding to the cell membrane, with the help of phosphoinositide‑dependent kinase, in the PI3K/Akt signal transduction pathway. Threonine and serine phosphorylation contribute to Akt translocation from the cytoplasm to the nucleus and further mediates enzymatic biological effects, including those involved in cell proliferation, apoptosis inhibition, cell migration, vesicle transport and cell cancerous transformation. As a key downstream protein of the PI3K/Akt signaling pathway, hypoxia‑inducible factor (HIF)‑1 is closely associated with the concentration of oxygen in the environment. Maintaining stable levels of HIF‑1 protein is critical under normoxic conditions; however, HIF‑1 levels quickly increase under hypoxic conditions. HIF‑1α is involved in the acute hypoxic response associated with erythropoietin, whereas HIF‑2α is associated with the response to chronic hypoxia. Furthermore, PI3K/Akt can reduce the synthesis of glycogen and increase glycolysis. Inhibition of glycogen synthase kinase 3β activity by phosphorylation of its N‑terminal serine increases accumulation of cyclin D1, which promotes the cell cycle and improves cell proliferation through the PI3K/Akt signaling pathway. The PI3K/Akt signaling pathway is closely associated with a variety of enzymatic biological effects and glucose metabolism.
Topics: Animals; Erythropoiesis; Glycolysis; Humans; Hypoxia; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 30535469
DOI: 10.3892/mmr.2018.9713 -
British Journal of Haematology Apr 2016Red blood cells (RBCs) are generated from haematopoietic stem and progenitor cells (HSPCs) through the step-wise process of differentiation known as erythropoiesis. In... (Review)
Review
Red blood cells (RBCs) are generated from haematopoietic stem and progenitor cells (HSPCs) through the step-wise process of differentiation known as erythropoiesis. In this review, we discuss our current understanding of erythropoiesis and highlight recent advances in this field. During embryonic development, erythropoiesis occurs in three distinct waves comprising first, the yolk sac-derived primitive RBCs, followed sequentially by the erythro-myeloid progenitor (EMP) and HSPC-derived definitive RBCs. Recent work has highlighted the complexity and variability that may exist in the hierarchical arrangement of progenitors responsible for erythropoiesis. Using recently defined cell surface markers, it is now possible to enrich for erythroid progenitors and precursors to a much greater extent than has been possible before. While a great deal of knowledge has been gained on erythropoiesis from model organisms, our understanding of this process is currently being refined through human genetic studies. Genes mutated in erythroid disorders can now be identified more rapidly by the use of next-generation sequencing techniques. Genome-wide association studies on erythroid traits in healthy populations have also revealed new modulators of erythropoiesis. All of these recent developments have significant promise not only for increasing our understanding of erythropoiesis, but also for improving our ability to intervene when RBC production is perturbed in disease.
Topics: Animals; Cell Communication; Cell Differentiation; Embryonic Development; Erythropoiesis; Hematologic Diseases; Hematopoietic Stem Cells; Hemoglobins; Heterografts; Humans; Mice; Models, Biological; Transcription, Genetic; Zebrafish
PubMed: 26846448
DOI: 10.1111/bjh.13938 -
Blood Apr 2022To enable effective oxygen transport, ∼200 billion red blood cells (RBCs) need to be produced every day in the bone marrow through the fine-tuned process of...
To enable effective oxygen transport, ∼200 billion red blood cells (RBCs) need to be produced every day in the bone marrow through the fine-tuned process of erythropoiesis. Erythropoiesis is regulated at multiple levels to ensure that defective RBC maturation or overproduction can be avoided. Here, we provide an overview of different layers of this control, ranging from cytokine signaling mechanisms that enable extrinsic regulation of RBC production to intrinsic transcriptional pathways necessary for effective erythropoiesis. Recent studies have also elucidated the importance of posttranscriptional regulation and highlighted additional gatekeeping mechanisms necessary for effective erythropoiesis. We additionally discuss the insights gained by studying human genetic variation affecting erythropoiesis and highlight the discovery of BCL11A as a regulator of hemoglobin switching through genetic studies. Finally, we provide an outlook of how our ability to measure multiple facets of this process at single-cell resolution, while accounting for the impact of human variation, will continue to refine our knowledge of erythropoiesis and how this process is perturbed in disease. As we learn more about this intricate and important process, additional opportunities to modulate erythropoiesis for therapeutic purposes will undoubtedly emerge.
Topics: Erythrocytes; Erythropoiesis; Gene Expression Regulation; Hemoglobins; Humans
PubMed: 34936695
DOI: 10.1182/blood.2021011044 -
Blood Nov 2022Anemia of inflammation (AI) is a highly prevalent comorbidity in patients affected by chronic inflammatory disorders, such as chronic kidney disease, inflammatory bowel... (Review)
Review
Anemia of inflammation (AI) is a highly prevalent comorbidity in patients affected by chronic inflammatory disorders, such as chronic kidney disease, inflammatory bowel disease, or cancer, that negatively affect disease outcome and quality of life. The pathophysiology of AI is multifactorial, with inflammatory hypoferremia and iron-restricted erythropoiesis playing a major role in the context of disease-specific factors. Here, we review the recent progress in our understanding of the molecular mechanisms contributing to iron dysregulation in AI, the impact of hypoferremia and anemia on the course of the underlying disease, and (novel) therapeutic strategies applied to treat AI.
Topics: Humans; Iron; Quality of Life; Anemia; Erythropoiesis; Inflammation; Chronic Disease
PubMed: 35994752
DOI: 10.1182/blood.2021013472 -
Blood Oct 2022The erythroblastic island (EBI), composed of a central macrophage surrounded by maturing erythroblasts, is the erythroid precursor niche. Despite numerous studies, its...
The erythroblastic island (EBI), composed of a central macrophage surrounded by maturing erythroblasts, is the erythroid precursor niche. Despite numerous studies, its precise composition is still unclear. Using multispectral imaging flow cytometry, in vitro island reconstitution, and single-cell RNA sequencing of adult mouse bone marrow (BM) EBI-component cells enriched by gradient sedimentation, we present evidence that the CD11b+ cells present in the EBIs are neutrophil precursors specifically associated with BM EBI macrophages, indicating that erythro-(myelo)-blastic islands are a site for terminal granulopoiesis and erythropoiesis. We further demonstrate that the balance between these dominant and terminal differentiation programs is dynamically regulated within this BM niche by pathophysiological states that favor granulopoiesis during anemia of inflammation and favor erythropoiesis after erythropoietin stimulation. Finally, by molecular profiling, we reveal the heterogeneity of EBI macrophages by cellular indexing of transcriptome and epitope sequencing of mouse BM EBIs at baseline and after erythropoietin stimulation in vivo and provide a searchable online viewer of these data characterizing the macrophage subsets serving as hematopoietic niches. Taken together, our findings demonstrate that EBIs serve a dual role as niches for terminal erythropoiesis and granulopoiesis and the central macrophages adapt to optimize production of red blood cells or neutrophils.
Topics: Animals; Mice; Epitopes; Erythroblasts; Erythropoiesis; Erythropoietin
PubMed: 35862735
DOI: 10.1182/blood.2022015724 -
Journal of the American Society of... Jun 2019
Topics: Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Renal Dialysis
PubMed: 31015256
DOI: 10.1681/ASN.2019030266 -
BioMed Research International 2015
Topics: Animals; Biological Evolution; Cell Differentiation; Cells, Cultured; Embryonic Development; Erythroblasts; Erythrocytes; Erythropoiesis; Gene Expression Regulation, Developmental; Hemoglobins; Humans; Mice; Phylogeny; Species Specificity
PubMed: 26576415
DOI: 10.1155/2015/136270 -
International Journal of Molecular... Oct 2022One of the major pathophysiologies of malaria is the development of anemia. Although hemolysis and splenic clearance are well described as causes of malarial anemia,... (Review)
Review
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 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 parasites may have on the suppression of erythropoiesis.
Topics: Animals; Humans; Erythropoiesis; Malaria; Plasmodium; Anemia; Bone Marrow
PubMed: 36361552
DOI: 10.3390/ijms232112762