Interleukin-33 contributes to anemia of chronic inflammation by inhibiting differentiation of erythroid progenitors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE141480 | GEO | 2020/05/15
REPOSITORIES: GEO
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Project description:Human CD71+ erythroid cells (CECs) have been recognized to have an immunoregulatory function via direct cell-cell interaction and soluble mediators such as arginase-2 and reactive oxygen species. Circulating CECs increase in healthy newborns or patients with hemolytic, malignant and cardiopulmonary disorders. To assess the pathophysiological role of CECs in inflammatory diseases, we studied the gene expression and function focusing on systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells obtained from patients with SoJIA expressed upregulated erythropoiesis-related genes, that determined the largest increase of circulating CECs during active phase SoJIA of all inflammatory diseases including polyarthritis, Kawasaki disease, bacteremia and systemic lupus erythematosus. Despite the opposite roles of erythropoietin and hepcidin in erythropoiesis, both serum levels positively correlated with the amounts of peripheral blood CECs in SoJIA patients. There were positive correlations between CECs and inflammatory markers of C-reactive protein, interleukin (IL)-6, IL-18, or soluble TNF receptor. Co-culture with active SoJIA-driven CECs significantly suppressed the secretion of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top of upregulated genes in SoJIA-driven CECs was ARG2 compared with those in CECs from cord blood controls. On the other hand, cytokine productions from monocytes were suppressed by co-culture even with an arginase inhibitor. CECs are mobilized to periphery in SoJIA for the control of excessive inflammation via the immuno-regulatory pathways partly involving arginase-2. Understanding the association between CECs and magnitude of systemic inflammation may clarify the unappreciated role of erythroid precursors in health and disease process of immune dysregulation.
2021-07-20 | GSE164120 | GEO
Project description:We previously identified inactivating mutations in roundabout guidance receptor 1 (ROBO1) in patients with myelodysplastic syndrome (MDS), which was associated with poor prognosis and susceptibility to acute myeloid leukemia (AML) transformation. Nonetheless, the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here we report that the ablation of Robo1 in mice is sufficient to confer MDS-like disease with anemia and multilineage dysplasia. More specifically, Robo1 deficiency impairs the self-renewal and differentiation capacity of hematopoietic stem progenitor cells (HSPCs) and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors (MEPs), which causes a blockage in the early stages of erythropoiesis in mice. Similarly, Robo1-deficienct HSPCs recapitulated MDS-like disease with anemia and multilineage dysplasia in transplanted mice. Correspondingly, clinical data also reveal that low expression of ROBO1 is associated with shortened survival, severe anemia and a high risk of AML transformation in patients with MDS. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-GTPase family, serves as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the proliferation of erythroid colonies in Robo1 deficient mice. In contrast, Cdc42 inhibitor (CASIN) effectively attenuates the erythroid colony formation of HSPCs. Collectively, our results suggest that Robo1 deficiency may provide a promising therapeutic target against MDS by impairing HSPC self-renewal and erythropoiesis via CDC42, predicting a poor prognosis for severe anemia and a high risk of AML transformation in MDS.
2023-12-01 | GSE231641 | GEO
Project description:Preeclampsia (PE) has been associated with placental dysfunction, resulting in foetal hypoxia, accelerated erythropoiesis and increased erythroblast count in the umbilical cord blood (UCB). Although the detailed effects remain unknown, placental dysfunction can also cause inflammation, nutritional and oxidative stress in the fetus that can affect erythropoiesis. Here, we compared the expression of surface adhesion molecules and erythroid differentiation capacity of UCB hematopoietic stem/ progenitor cells (HSPCs), UCB erythroid profiles along with transcriptome and proteome of these cells between male and female foetuses from PE and normotensive pregnancies. While no significant differences were observed in UCB HSPC migration/ homing and in vitro erythroid colony differentiation, the UCB HSPC transcriptome and the proteomic profile of the in vitro differentiated erythroid cells differed between PE vs normotensive samples. Accordingly, despite absence of significant differences in the UCB erythroid populations in male or female foetuses from PE or normotensive pregnancies, transcriptional changes were observed during erythropoiesis, particularly affecting male foetuses. Pathway analysis suggested deregulation in mTORC1/AMPK signaling pathways controlling cell cycle, differentiation and protein synthesis. These results associate PE with transcriptional and proteomic changes in foetal HSPCs and erythroid cells that may underlie the higher erythroblast count in the UCB in PE.
2019-06-20 | PXD010364 | Pride
Project description:Hypoxia is associated with increased erythropoietin (EPO) release to drive erythropoiesis. However, a prolonged sojourn at high altitude results in an increase in EPO levels followed by a decrease, although erythropoiesis remains elevated at a stable level. The role of hypoxia and related EPO adjustments are not fully understood and contributed to the formulation of the theory of neocytolysis. In this study, we aimed to exclusively evaluate the role of oxygen on erythropoiesis comparing in vitro erythroid differentiation performed at atmospheric oxygen, with a lower oxygen concentration (3% O2) and with cultures of erythroid precursors isolated from peripheral blood after a 19-day sojourn at high altitude (3450 m). Results highlight an accelerated erythroid maturation at low oxygen and more concave morphology of reticulocytes. No differences in deformability were observed in the formed reticulocytes in the tested conditions. Moreover, hematopoietic stem and progenitor cells isolated from blood affected by hypoxia at high altitude did not result in a different erythroid development, suggesting no retention of high altitude signature but rather an immediate adaptation to oxygen concentration. This adaptation was observed during in vitro erythropoiesis at 3% oxygen, displaying a significantly increased glycolytic metabolic profile. These hypoxia-induced effects on in vitro erythropoiesis fail to provide an intrinsic explanation to the concept of neocytolysis.
2022-04-06 | PXD031776 | Pride
Project description:Burst-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E) cells are erythroid progenitors traditionally defined by colony assays. We developed a flow cytometry-based strategy for isolating human BFU-E and CFU-E cells based on the changes in expression of cell surface markers during in vitro erythroid cell culture. BFU-E and CFU-E are characterized by CD45+GPA-IL-3R-CD34+CD36-CD71low and CD45+GPA-IL-3R-CD34-CD36+CD71high phenotypes, respectively. Colony assays validated phenotypic assignment giving rise to BFU-E and CFU-E colonies, both at a purity ~90%. The BFU-E colony forming ability of CD45+GPA-IL-3R-CD34+CD36-CD71low cells required SCF and erythropoietin, while the CFU-E colony forming ability of CD45+GPA-IL-3R-CD34-CD36+CD71high cells required only erythropoietin. Bioinformatic analysis of the RNA-seq data revealed unique transcriptomes in each differentiation stage. The sorting strategy was validated in uncultured primary cells isolated from bone marrow and peripheral blood, indicating that marker expression is not an artifact of in vitro cell culture, but represents an in vivo characteristic of erythroid progenitor populations. The ability to isolate highly pure human BFU-E and CFU-E progenitors will enable detailed cellular and molecular characterization of these distinct progenitor populations and define their contribution to disordered erythropoiesis in inherited and acquired hematological disease. Our data provide important resource for future studies. Transcription profiles of Human erythroid progenitors at distinct developmental stages were generated by deep sequencing, in triplicate, using IlluminaHiSeq 2000. The complete dataset comprises 4 sample types: CD34, BFU, CFU, and Pro (reanalysis of GSM1304777-GSM1304779).
2014-10-30 | E-GEOD-61566 | biostudies-arrayexpress
Project description:Acute anemia induces rapid expansion of erythroid precursors and accelerated differentiation to replenish erythrocytes. Paracrine signals – involving cooperation between SCF/c-Kit signaling and other signaling inputs – are required for the activation and function of erythroid precursors in anemia. Our prior work revealed that the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene is transcriptionally upregulated in a model of acute anemia. Samd14 expression increases the regenerative capacity of the erythroid system and promotes stress-dependent c-Kit signaling. However, the mechanism underlying Samd14’s role in stress erythropoiesis is unknown. We identified a protein-protein interaction between Samd14 and the α- and β heterodimers of the F-actin capping protein (CP) complex. Knockdown of the CP β subunit increased erythroid maturation in ex vivo cultures and decreased colony forming potential of stress erythroid precursors. In a genetic complementation assay for Samd14 activity, our results revealed that the Samd14-CP interaction is a determinant of erythroid precursor cell levels and function. Samd14-CP promotes SCF/c-kit signaling in CD71med spleen erythroid precursors.
2022-08-09 | PXD030467 | Pride
Project description:In recent years, general hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) enzyme inhibitors have been developed for the treatment of anemia due to renal disease and osteoporosis. However, it remains a challenge to target the HIF signaling pathway without dysregulating the skeletal and hematopoietic system. Here, we examined the effects of Vhl deletion in bone by performing longitudinal analyses of VhlcKO mice at 3, 6, 10, and 24 weeks of age, where at 10 and 24 weeks of age, high bone mass and splenomegaly are present. Using flow cytometry, we observed increased frequency (%) of CD71loTER119hiFSClo orthochromatophilic erythroblasts and reticulocytes in 10- and 24-week-old VhlcKO bone marrow (BM), which correlated with elevated erythropoietin levels in the BM and increased number of red blood cells in circulation. The absolute numbers of myeloerythroid progenitors (MEPs) in the BM were significantly reduced at 24 weeks. Bulk RNA-Seq of the MEPs showed upregulation of Epas1 (Hif1a) and Efnb2 (Hif2a) in VhlcKO MEPs, consistent with a response to hypoxia, and genes involved in erythrocyte development, actin filament organization, and response to glucose.Additionally, histological analysis of VhlcKO spleens revealed red pulp hyperplasia and the presence of megakaryocytes, both of which are features of extramedullary hematopoiesis (EMH). EMH in the spleen was correlated with the presence of mature stress erythroid progenitors, suggesting that stress erythropoiesis is occurring to compensate for the BM microenvironmental irregularities. Our studies implicate that HIF-driven alterations in skeletal homeostasis can accelerate erythropoiesis.
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2023-01-25 | MSV000091139 | MassIVE
Project description:Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the Samd14 locus (S14E) is required for survival in severe anemia. The S14E contains DNA binding motifs for GATA and TAL1, two transcription factors which bind to the enhancer and activate transcription during stress erythropoiesis. However, Samd14 is only one of dozens of anemia-activated genes. In a mouse model of acute anemia, we used single cell RNA sequencing to identify erythroid cell types which expanded and increased expression of genes that contain S14E-like cis-elements. Through orthogonal loss-of-function approaches (shRNA, sgRNA-guided Cas9 and Cas9-KRAB), we reveal that several S14E-like cis-elements are important for the expression of newly identified anemia induced genes, including the poorly studied Ssx-2 interacting protein (Ssx2ip). Ssx2ip expression was determined to play an important role in erythroid progenitor activity, cell cycle progression, and proliferation in anemia. Our results define a genome-wide mechanism in which S14E-like enhancers control transcriptional responses during erythroid regeneration. Furthermore, time course analysis of erythroid precursor gene activation in anemia revealed distinct transcriptional programs are established at earlier time points, distinct from S14E-like elements. These findings provide a framework to understand anemia-specific transcriptional mechanisms, ineffective erythropoiesis, anemia recovery and phenotypic variability within human populations.
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