Transferrin receptor 2 is a component of the erythropoietin receptor complex and is required for efficient erythropoiesis

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5357-5367 ◽  
Author(s):  
Hana Forejtnikovà ◽  
Maud Vieillevoye ◽  
Yael Zermati ◽  
Mireille Lambert ◽  
Rosa Maria Pellegrino ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Hepatic Function ◽  
Erythropoietin Receptor ◽  
Erythroid Cells ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
Associated Proteins

Abstract Erythropoietin (Epo) is required for erythroid progenitor differentiation. Although Epo crosslinking experiments have revealed the presence of Epo receptor (EpoR)–associated proteins that could never be identified, EpoR is considered to be a paradigm for homodimeric cytokine receptors. We purified EpoR-binding partners and identified the type 2 transferrin receptor (TfR2) as a component of the EpoR complex corresponding to proteins previously detected in cross-linking experiments. TfR2 is involved in iron metabolism by regulating hepcidin production in liver cells. We show that TfR2 and EpoR are synchronously coexpressed during the differentiation of erythroid progenitors. TfR2 associates with EpoR in the endoplasmic reticulum and is required for the efficient transport of this receptor to the cell surface. Erythroid progenitors from TfR2−/−mice show a decreased sensitivity to Epo and increased circulating Epo levels. In human erythroid progenitors, TfR2 knockdown delays the terminal differentiation. Erythroid cells produce growth differentiation factor-15, a cytokine that suppresses hepatic hepcidin production in certain erythroid diseases such as thalassemia. We show that the production of growth differentiation factor-15 by erythroid cells is dependent on both Epo and TfR2. Taken together, our results show that TfR2 exhibits a non hepatic function as a component of the EpoR complex and is required for efficient erythropoiesis.

scholarly journals Gdf15 regulates murine stress erythroid progenitor proliferation and the development of the stress erythropoiesis niche

2019 ◽  
Vol 3 (14) ◽  
pp. 2205-2217 ◽  
Author(s):  
Siyang Hao ◽  
Jie Xiang ◽  
Dai-Chen Wu ◽  
James W. Fraser ◽  
Baiye Ruan ◽  
...  
Keyword(s):  
Steady State ◽  
Essential Role ◽  
Metabolic Enzymes ◽  
Metabolic Status ◽  
Erythroid Cells ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Growth Differentiation Factor 15 ◽  
Stress Erythropoiesis ◽  
Murine Spleen

Abstract Anemic stress induces the proliferation of stress erythroid progenitors in the murine spleen that subsequently differentiate to generate erythrocytes to maintain homeostasis. This process relies on the interaction between stress erythroid progenitors and the signals generated in the splenic erythroid niche. In this study, we demonstrate that although growth-differentiation factor 15 (Gdf15) is not required for steady-state erythropoiesis, it plays an essential role in stress erythropoiesis. Gdf15 acts at 2 levels. In the splenic niche, Gdf15−/− mice exhibit defects in the monocyte-derived expansion of the splenic niche, resulting in impaired proliferation of stress erythroid progenitors and production of stress burst forming unit-erythroid cells. Furthermore, Gdf15 signaling maintains the hypoxia-dependent expression of the niche signal, Bmp4, whereas in stress erythroid progenitors, Gdf15 signaling regulates the expression of metabolic enzymes, which contribute to the rapid proliferation of stress erythroid progenitors. Thus, Gdf15 functions as a comprehensive regulator that coordinates the stress erythroid microenvironment with the metabolic status of progenitors to promote stress erythropoiesis.

scholarly journals Association of growth-differentiation factor-15 with the number of circulating proangiogenic endothelial progenitor cells in patients with type 2 diabetes mellitus

2018 ◽  
Vol 5 (7) ◽  
pp. 2480-2492
Author(s):  
Alexander E. Berezin ◽  
Alexander A. Kremzer ◽  
Daniel Petrovich ◽  
Ioana Mozos ◽  
Alexander A. Berezin
Keyword(s):  
Logistic Regression ◽  
Healthy Volunteers ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Endothelial Progenitor ◽  
Growth Differentiation Factor 15 ◽  
Type 2 Dm ◽  
Differentiation Factor ◽  
Hs Crp

The objective: to investigate the relationship between levels of growth differentiation factor-15 (GDF-15) and circulating number of endothelial progenitor cells (EPCs) with angiopoietin phenotypes: CD34+CD14+CD309+, and CD34+CD14+CD309+Tie2+ in patients with type 2 DM. Methods: The study was retrospectively involved 76 patients with type 2 DM aged 38 to 55 years and 30 healthy volunteers. Data collection included demographic and anthropometric information, hemodynamic performances and biomarkers of the diseases. Flow cytometry was used to determine EPCs' populations. Results: The levels of GDF-15 in peripheral blood of diabetics associated with age (r = 0.31, P = 0.044), high-sensitive C-reactive protein [hs-CRP] (r = 0.40, P = 0.001), smoking (r = 0.38, P = 0.001), body mass index [BMI] (r = 0.34, P = 0.001), LDL cholesterol (r = 0.28, P = 0.001), glycated hemoglobin [HbA1c] (r = -0.28, P = 0.001), number of CV risk factors (r = 0.26, P = 0.001). In univariate logistic regression analysis we found that level of GDF-15 ≥ 618 pg/mL, hs-CRP ≥7.12 mg/L, HbA1c ≥6.4%, fasting glucose ≥6.7 mmol/L, and BMI ≥27.3 kg/m2 predicted deficiency of both angiopoetic phenotypes of EPCs. In multivariate logistic regression model GDF-15 ≥618 pg/mL demonstrated the best odds ratio values for declining of EPCs in diabetics in comparison with other predictors including BMI, HbA1c and hs-CRP. Conclusion: GDF-15 was remarkably evaluated in type 2 DM population to healthy volunteers, and it was an independent factor that contributes to mobilization and probably proliferation of endothelial precursors with high angiopoetic activity.

scholarly journals A constitutively activated erythropoietin receptor stimulates proliferation and contributes to transformation of multipotent, committed nonerythroid and erythroid progenitor cells.

1994 ◽  
Vol 14 (4) ◽  
pp. 2266-2277 ◽  
Author(s):  
G D Longmore ◽  
P N Pharr ◽  
H F Lodish
Keyword(s):  
Cell Line ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Leukemia Virus ◽  
Active Form ◽  
Erythropoietin Receptor ◽  
Mutant Form ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

If the env gene of spleen focus-forming virus (SFFV) is replaced by a cDNA encoding a constitutively active form of the erythropoietin receptor, EPO-R(R129C), the resultant recombinant virus, SFFVcEPO-R, induces transient thrombocytosis and erythrocytosis in infected mice. Clonogenic progenitor cell assays of cells from the bone marrow and spleens of these infected mice suggest that EPO-R(R129C) can stimulate proliferation of committed megakaryocytic and erythroid progenitors as well as nonerythroid multipotent progenitors. From the spleens of SFFVcEPO-R-infected mice, eight multiphenotypic immortal cell lines were isolated and characterized. These included primitive erythroid, lymphoid, and monocytic cells. Some expressed proteins characteristic of more than one lineage. All cell lines resulting from SFFVcEPO-R infection contained a mutant form of the p53 gene. However, in contrast to infection by SFFV, activation of PU.1 gene expression, by retroviral integration, was not observed. One cell line had integrated a provirus upstream of the fli-1 gene, in a location typically seen in erythroleukemic cells generated by Friend murine leukemia virus infection. This event led to increased expression of fli-1 in this cell line. Thus, infection by SFFVcEPO-R can induce proliferation and lead to transformation of nonerythroid as well as very immature erythroid progenitor cells. The sites of proviral integration in clonal cell lines are distinct from those in SFFV-derived lines.

Decreased Serum Growth Differentiation Factor 15 Levels After Lifestyle Intervention in Patients With Newly Diagnosed Type 2 Diabetes Mellitus

2020 ◽  
Author(s):  
Xingxing He ◽  
Jiaorong Su ◽  
Xiaojing Ma ◽  
Jingyi Lu ◽  
Yufei Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lifestyle Intervention ◽  
Enzyme Linked Immunosorbent Assay ◽  
Oral Glucose ◽  
Model Assessment ◽  
Newly Diagnosed ◽  
Serum Samples ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

Abstract Background: Recent studies noted that circulating growth differentiation factor 15 (GDF15) were closely related to metabolic states. The study aimed to explore the changes of GDF15 levels and their influencing factors after 4 weeks of lifestyle intervention (LI) or LI combined with breakfast meal replacement (LI+MR) in newly diagnosed type 2 diabetes patients. Methods: A total of 84 patients with available serum samples at both baseline and Week 4 were enrolled in this biomarker substudy. All subjects underwent a 2-hour 75g oral glucose tolerance test at baseline and Week 4. Serum GDF15 levels were determined by a sandwich enzyme-linked immunosorbent assay. Results: After 4-weeks of LI, GDF15 levels overall significantly decreased compared with baseline (P<0.05). ∆GDF15 levels were significantly and negatively associated with baseline GDF15 levels (r=–0.450, P<0.001). The optimal cut-off point of baseline GDF15 levels for predicting a GDF15 decrease after 4-weeks of LI was 904.57 pg/ml, with an area under curve of 0.699. Based on the cut-off point of 900 pg/ml, patients with baseline GDF15 ≥900 pg/ml had significantly decreased GDF15 levels after LI, while those <900 pg/ml had no significant changes. Regression models showed that baseline GDF15 level was an independent positive factor for the improvement of fasting plasma glucose and homeostasis model assessment for insulin resistance only in patients with baseline GDF15 levels ≥900 pg/ml. Conclusions: LI led to significantly decreased GDF15 levels among patients with newly diagnosed type 2 diabetes and its effect was more significant among patients with baseline GDF15 levels ≥900 pg/ml.Trial registration: ClinicalTrials.gov, NCT02248714. Registered 25 September 2014 - Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02248714?term=NCT02248714&draw=2&rank=1

scholarly journals Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia

2016 ◽  
Vol 40 (1) ◽  
pp. 70 ◽  
Author(s):  
Ji Min Kim ◽  
Min Kyung Back ◽  
Hyon-Seung Yi ◽  
Kyong Hye Joung ◽  
Hyun Jin Kim ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

scholarly journals Growth-Differentiation Factor 15 Predicts Worsening of Albuminuria in Patients With Type 2 Diabetes

Diabetes Care ◽  
2012 ◽  
Vol 35 (11) ◽  
pp. 2340-2346 ◽  
Author(s):  
M. E. Hellemons ◽  
M. Mazagova ◽  
R. T. Gansevoort ◽  
R. H. Henning ◽  
D. de Zeeuw ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

scholarly journals TAF10 Interacts with GATA1 Transcription Factor and Controls Mouse Erythropoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2912-2912
Author(s):  
Petros Papadopoulos ◽  
Laura Gutierrez ◽  
Jeroen Demmers ◽  
Dimitris Papageorgiou ◽  
Elena Karkoulia ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fetal Liver ◽  
Erythroid Differentiation ◽  
Erythroid Cells ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Fetal Liver Cells ◽  
Gata1 Transcription Factor

Abstract The ordered assembly of a functional preinitiation complex (PIC), composed of general transcription factors (GTFs) is a prerequisite for the transcription of protein coding genes by RNA polymerase II. TFIID, comprised of the TATA binding protein (TBP) and 13 TBP-associated factors (TAFs), is the GTF that is thought to recognize the promoter sequences allowing site-specific PIC assembly. Transcriptional cofactors, such as SAGA (Spt-Ada-Gcn5-acetyltransferase), are also necessary to have tightly regulated transcription initiation. However, a new era on the role of the GTFs and specifically on the role of TFIID in tissue specific and promoter specific transcriptional regulation has emerged in the light of novel findings regarding the differentiation programs of different cell types1. TAF10 is a subunit of both the TFIID and the SAGA co-activator HAT complexes2. The role of TAF10 is indispensable for early embryonic transcription and mouse development as knockout (KO) embryos die early in gestation between E3.5 and E5.5, around the stage when the supply of maternal protein becomes insufficient3. However, when analyzing TFIID stability and transcription it was noted that not all cells and tissues were equally affected by the loss of TAF10. The contribution of the two TAF10-containing complexes (TFIID, SAGA) to erythropoiesis remains elusive. Ablation of TAF10 specifically in erythroid cells by crossing the TAF10-Lox with the EpoR-Cre mouse led to a differentiation block at around E13.5 with erythroid progenitor cells accumulating at a higher percentage (26% in the KO embryos vs 16% in the WTs at E12.5) at the double positive stage KIT+CD71+ and giving rise to fewer mature TER119+ cells in the fetal liver. At E13.5 embryos were dead with almost no erythroid cells in the fetal liver. Gene expression analysis of the fetal liver cells of the embryos revealed down-regulation of GATA1 expression and its target genes, bh1&bmaj/min globins and KLF1 transcription factor while expression of other genes known to have a role in mouse hematopoiesis remained unaffected (MYB, GATA2, PU.1). In order to get insight to the role of TAF10 during erythropoiesis we analyzed the composition of both TAF10-containing complexes (TFIID and SAGA) by mass spectrometry. We found that their stoichiometry changes slightly but not fundamentally during erythroid differentiation and development (human fetal liver erythroid progenitors, human blood erythroid progenitors and mouse erythroid progenitor cells) and no major rearrangements were generated in the composition of the TFIID as it was reported in other cell differentiation programs (e.g. skeletal differentiation, hepatogenesis). Additionally, we found GATA1 transcription factor only in the fetal liver and not in the adult erythroid cells in the mass spectrometry data of TAF10 immunoprecipitations (IPs), an interaction that we confirmed by reciprocal IP of TAF10 and GATA1 in MEL and mouse fetal liver cells. Most importantly, we checked whether TAF10 binding is enriched on the GATA1 locus in human erythroid cells during the fetal and the adult stage in erythroid proerythroblasts and we found that there is enriched binding of TAF10 in the palindromic GATA1 site in the fetal stage. Our results support a developmental role for TAF10 in GATA1 regulated genes, including GATA1 itself, during erythroid differentiation emphasizing the crosstalk between the transcriptional machinery and activators in erythropoiesis. References 1. Goodrich JA, Tjian R (2010) Unexpected roles for core promoter recognition factors in cell-type-specific transcription and gene regulation. Nature reviews Genetics 11: 549-558 2 .Timmers HT, Tora L (2005) SAGA unveiled. Trends Biochem Sci 30: 7-10 3. Mohan WS, Jr., Scheer E, Wendling O, Metzger D, Tora L (2003) TAF10 (TAF(II)30) is necessary for TFIID stability and early embryogenesis in mice. Mol Cell Biol 23: 4307-4318 Disclosures No relevant conflicts of interest to declare.

scholarly journals Erythroblastic Island Macrophages Shape Normal Erythropoiesis and Drive Associated Disorders in Erythroid Hematopoietic Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Wei Li ◽  
Rongqun Guo ◽  
Yongping Song ◽  
Zhongxin Jiang
Keyword(s):  
Steady State ◽  
Historical Data ◽  
Erythropoietin Receptor ◽  
Erythroid Cells ◽  
Erythroid Progenitors ◽  
Hematological Disorders ◽  
Macrophage Dysfunction ◽  
Hematopoietic Disorders ◽  
Functional Analyses ◽  
New Hypothesis

Erythroblastic islands (EBIs), discovered more than 60 years ago, are specialized microenvironments for erythropoiesis. This island consists of a central macrophage with surrounding developing erythroid cells. EBI macrophages have received intense interest in the verifications of the supporting erythropoiesis hypothesis. Most of these investigations have focused on the identification and functional analyses of EBI macrophages, yielding significant progresses in identifying and isolating EBI macrophages, as well as verifying the potential roles of EBI macrophages in erythropoiesis. EBI macrophages express erythropoietin receptor (Epor) both in mouse and human, and Epo acts on both erythroid cells and EBI macrophages simultaneously in the niche, thereby promoting erythropoiesis. Impaired Epor signaling in splenic niche macrophages significantly inhibit the differentiation of stress erythroid progenitors. Moreover, accumulating evidence suggests that EBI macrophage dysfunction may lead to certain erythroid hematological disorders. In this review, the heterogeneity, identification, and functions of EBI macrophages during erythropoiesis under both steady-state and stress conditions are outlined. By reviewing the historical data, we discuss the influence of EBI macrophages on erythroid hematopoietic disorders and propose a new hypothesis that erythroid hematopoietic disorders are driven by EBI macrophages.

Sign in / Sign up

Export Citation Format

Share Document