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Journal of Cellular Physiology Jul 2021Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of... (Review)
Review
Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.
Topics: Bone Morphogenetic Proteins; Erythroblasts; Erythropoiesis; Hepcidins; Homeostasis; Humans; Iron; Iron Overload; Peptide Hormones; Protein Conformation; Signal Transduction
PubMed: 33372284
DOI: 10.1002/jcp.30247 -
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 -
Genome Biology Mar 2018Despite the many approaches to study differential splicing from RNA-seq, many challenges remain unsolved, including computing capacity and sequencing depth requirements....
Despite the many approaches to study differential splicing from RNA-seq, many challenges remain unsolved, including computing capacity and sequencing depth requirements. Here we present SUPPA2, a new method that addresses these challenges, and enables streamlined analysis across multiple conditions taking into account biological variability. Using experimental and simulated data, we show that SUPPA2 achieves higher accuracy compared to other methods, especially at low sequencing depth and short read length. We use SUPPA2 to identify novel Transformer2-regulated exons, novel microexons induced during differentiation of bipolar neurons, and novel intron retention events during erythroblast differentiation.
Topics: Alternative Splicing; Cell Line; Erythroblasts; Exons; Humans; Neurons; Sequence Analysis, RNA; Software
PubMed: 29571299
DOI: 10.1186/s13059-018-1417-1 -
Cell Stem Cell Aug 2022Reprogramming somatic cells into megakaryocytes (MKs) would provide a promising source of platelets. However, using a pharmacological approach to generate human MKs from...
Reprogramming somatic cells into megakaryocytes (MKs) would provide a promising source of platelets. However, using a pharmacological approach to generate human MKs from somatic cells remains an unmet challenge. Here, we report that a combination of four small molecules (4M) successfully converted human cord blood erythroblasts (EBs) into induced MKs (iMKs). The iMKs could produce proplatelets and release functional platelets, functionally resembling natural MKs. Reprogramming trajectory analysis revealed an efficient cell fate conversion of EBs into iMKs by 4M via the intermediate state of bipotent precursors. 4M induced chromatin remodeling and drove the transition of transcription factor (TF) regulatory network from key erythroid TFs to essential TFs for megakaryopoiesis, including FLI1 and MEIS1. These results demonstrate that the chemical reprogramming of cord blood EBs into iMKs provides a simple and efficient approach to generate MKs and platelets for clinical applications.
Topics: Blood Platelets; Cell Differentiation; Erythroblasts; Fetal Blood; Humans; Megakaryocytes
PubMed: 35931032
DOI: 10.1016/j.stem.2022.07.004 -
Nature Communications Nov 2023Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of...
Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determine that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (~26%), while erythroblasts contribute 1-4% of cfDNA in healthy individuals. Surprisingly, we discover that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.
Topics: Humans; Megakaryocytes; Thrombopoiesis; Erythropoiesis; Cell-Free Nucleic Acids; Blood Platelets; Erythroblasts; DNA
PubMed: 37985773
DOI: 10.1038/s41467-023-43310-2 -
Cell Reports. Medicine May 2023Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver...
Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1 macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.
Topics: Child; Humans; Child, Preschool; Erythroblasts; Hepatoblastoma; Hepatitis A Virus Cellular Receptor 2; Erythropoiesis; Liver Neoplasms; Tumor Microenvironment
PubMed: 37196629
DOI: 10.1016/j.xcrm.2023.101044 -
American Journal of Hematology Jun 2022
Topics: Erythroblasts; Erythropoiesis; Humans
PubMed: 34826173
DOI: 10.1002/ajh.26425 -
Nature Communications Dec 2021The erythroid terminal differentiation program couples sequential cell divisions with progressive reductions in cell size. The erythropoietin receptor (EpoR) is... (Randomized Controlled Trial)
Randomized Controlled Trial
The erythroid terminal differentiation program couples sequential cell divisions with progressive reductions in cell size. The erythropoietin receptor (EpoR) is essential for erythroblast survival, but its other functions are not well characterized. Here we use Epor mouse erythroblasts endowed with survival signaling to identify novel non-redundant EpoR functions. We find that, paradoxically, EpoR signaling increases red cell size while also increasing the number and speed of erythroblast cell cycles. EpoR-regulation of cell size is independent of established red cell size regulation by iron. High erythropoietin (Epo) increases red cell size in wild-type mice and in human volunteers. The increase in mean corpuscular volume (MCV) outlasts the duration of Epo treatment and is not the result of increased reticulocyte number. Our work shows that EpoR signaling alters the relationship between cycling and cell size. Further, diagnostic interpretations of increased MCV should now include high Epo levels and hypoxic stress.
Topics: Adult; Animals; Antigens, CD; CD4 Antigens; Cell Cycle; Cell Differentiation; Cell Nucleus; Cell Size; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; Embryo, Mammalian; Erythroblasts; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Fetus; Healthy Volunteers; Humans; Iron; Liver; Male; Mice, Inbred C57BL; Models, Biological; Protein Serine-Threonine Kinases; Receptors, Erythropoietin; Receptors, Transferrin; Reticulocytes; Signal Transduction; bcl-X Protein; Mice
PubMed: 34921133
DOI: 10.1038/s41467-021-27562-4 -
Haematologica Dec 2010
Topics: Animals; Cell Nucleus; Chromatin; Erythroblasts; Female; Histone Deacetylase 2; Male; Pregnancy
PubMed: 21123437
DOI: 10.3324/haematol.2010.033225 -
Current Opinion in Hematology May 2014This review summarizes our current understanding of the roles of Rho GTPases in early erythropoiesis, downstream of cytokine signaling, and in terminal erythroblast... (Review)
Review
PURPOSE OF REVIEW
This review summarizes our current understanding of the roles of Rho GTPases in early erythropoiesis, downstream of cytokine signaling, and in terminal erythroblast maturation and enucleation, as master regulators of the cytoskeleton and cytokinesis.
RECENT FINDINGS
Similarities of structural and signaling requirements of erythroblast enucleation with the cytokinesis process have been confirmed and expanded in the last year, suggesting that enucleation is a form of asymmetric cell division. Myosin, the classic actin partner in cytokinesis, was shown to play an essential role in enucleation. Studies with multispectral high-speed cell imaging in flow demonstrated a sequential process requiring establishment of polarity through a unipolar microtubule spindle in orthochromatic erythroblasts, followed by Rac-directed formation of a contractile actomyosin ring and coalescence of lipid rafts between reticulocyte and pyrenocyte, steps which reiterate the choreography of cytokinesis. mDia2, a Rho effector known to play a role in enucleation, was also found essential for erythroblast cytokinesis as its deficiency in mice caused failure of primitive erythropoiesis and embryonic death.
SUMMARY
Further elucidation of the role of Rho GTPases in the erythroid lineage development may reveal potential targets for improving red blood cell production in vivo and in vitro.
Topics: Animals; Biological Transport; Cytokines; Cytokinesis; Cytoskeleton; Erythroblasts; Erythropoiesis; Humans; Signal Transduction; rho GTP-Binding Proteins
PubMed: 24492678
DOI: 10.1097/MOH.0000000000000032