RNA Binding Protein SRSF3 confers an essential role in megakaryocyte maturation and platelet production
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE155620 | GEO | 2021/12/21
REPOSITORIES: GEO
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Project description:RNA Binding Protein SRSF3 confers an essential role in megakaryocyte maturation and platelet production
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Project description:RNA-seq expression analysis of transcripts encoding proteasome subunits in human CD34+ cord blood cell-derived megakaryocytes and mouse bone marrow-derived megakaryocytes. Analysis of transcript expression in human CD34+ cord blood cell-derived megakaryocytes and mouse bone marrow-derived megakaryocytes.
2015-01-31 | E-GEOD-58202 | biostudies-arrayexpress
Project description:Dnm2fl/fl Pf4-Cre (Dnm2Plt-/-) mice lacking the endocytic GTPase dynamin 2 (DNM2) in platelets and megakaryocytes (MKs) develop hallmarks of myelofibrosis. At the cellular level, the tyrosine kinase JAK2 is constitutively active but decreased in expression in Dnm2Plt-/- platelets. Additionally, Dnm2Plt-/- platelets cannot endocytose the thrombopoietin (TPO) receptor Mpl, leading to elevated circulating TPO levels. Here, we assessed whether the hyperproliferative phenotype of Dnm2Plt-/- mice was due to JAK2 constitutive activation or elevated circulating TPO levels. In unstimulated Dnm2Plt-/- platelets, STAT3 and to a lower extent STAT5 were phosphorylated, but their phosphorylation was slowed and diminished upon TPO stimulation. We further crossed Dnm2Plt-/- mice in the Mpl-/- background to generate Mpl-/- Dnm2Plt-/- mice lacking Mpl ubiquitously and DNM2 in platelets and MKs. Mpl-/- Dnm2Plt-/- platelets had severely reduced JAK2 and STAT3 but normal STAT5 expression. Mpl-/- Dnm2Plt-/- mice had severely reduced bone marrow MK and hematopoietic stem and progenitor cell numbers. Additionally, Mpl-/- Dnm2Plt-/- mice had severe erythroblast maturation defects, decreased expression of hemoglobin and heme homeostasis genes, increased expression of ribosome biogenesis and protein translation genes, and developed anemia with grossly elevated plasma erythropoietin levels, leading to early fatality by postnatal day 25. Mpl-/- Dnm2Plt+/+ mice had impaired EB development at three weeks of age, which normalized with adulthood. Together, the data shows that DNM2-dependent Mpl-mediated endocytosis in platelets and MKs is required for steady-state hematopoiesis and provides novel insights into a developmentally controlled role for Mpl in normal erythropoiesis, regulating hemoglobin and heme production.
2022-08-25 | GSE206343 | GEO
Project description:The hematopoietic system gives rise to a heterogeneous population of terminally differentiated cells that reside in the bone marrow (BM) to fulfill their roles in immunity, blood clotting and tissue oxygenation. Hematopoietic stem and progenitor cells are at the apex of a hierarchically organized maturation cascade constantly replenishing the pool of differentiated cells to maintain blood cell homeostasis. The bone marrow microenvironment is functionally compartmentalized by heterogeneous niche cells that provide physical and soluble signals to spatio-temporally organize hematopoiesis. Megakaryocytes (MKs) are niche cells of hematopoietic origin that support hematopoietic stem cell (HSCs) homeostasis and generate circulating platelets. Platelet production involves the release of MK fragments while their cell body is entirely consumed in a process termed thrombopoiesis. Consequently, replenishment of fragmented MKs from MK progenitors (termed megakaryopoiesis) is required to ensure sufficient platelet production, but also to maintain MK homeostasis within the HSC niche. Here, we used intravital imaging of the megakaryocytic lineage to identify the spatio-temporal patterns of megakaryopoiesis during steady state and thrombocytopenia. We show that MK consumption during thrombopoiesis is compensated by immediate and local proliferation of MK progenitors. MK homeostasis is controlled by plasmacytoid dendritic cells (pDCs) that scan the BM and secrete Interferon alpha (INFa) upon detection of exhausted megakaryocytes to trigger megakaryopoiesis. We identified local pDC-derived INFa release as a physiological inflammatory stimulus of the bone marrow niche that synchronizes megakaryopoiesis and thrombopoiesis to maintain homeostasis of MKs and platelets in steady state and under stress. Viral infection with SARS-CoV-2 can manipulate pDC-driven MK proliferation leading to inappropriate megakaryopoiesis, which has been associated with thrombotic complications during COVID-19.
2024-04-26 | GSE185488 | GEO
Project description:RNA-seq expression analysis of transcripts encoding proteasome subunits in human CD34+ cord blood cell-derived megakaryocytes and mouse bone marrow-derived megakaryocytes.
2015-01-31 | GSE58202 | GEO
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Project description:Circulating nucleic acids are present in plasma and are derived from a range of cell types, mainly cells of hematopoietic origin, enabling their use as biomarkers for diseases involving these cell types. Using cell type-specific methylation markers, we determined that megakaryocytes are major contributors to cfDNA (~26%), while erythroblasts contribute 1-4% of cfDNA in healthy individuals. Additionally, we identified megakaryocyte-derived DNA within platelets, providing non-invasive access to the megakaryocyte genome and epigenome. Analysis of cfDNA in women who have received male platelet transfusions indicates that megakaryocyte-derived cfDNA does not originate from platelets but is rather released directly from megakaryocytes. The concentration of megakaryocyte-derived cfDNA is elevated in individuals with pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased by bone marrow suppression (due to chemotherapy), while erythrocyte progenitor cfDNA is elevated in patients with Thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns may serve as novel biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis.
2022-10-12 | GSE206818 | GEO
Project description:Platelets play an important role in primary hemostasis, inflammation , (tumor) angiogenesis and cancer metastasis. Platelets are produced by megakaryocytes in the bone marrow and contain numerous bioactive proteins (e.g. growth factors, chemokine’s and proteases). These proteins inside platelets are either synthesized by the parental megakaryocytes or absorbed from the (micro)circulation. Therefore, it was postulated that changes in platelet protein content might indicate the presence or recurrence of a malignant tumor. We followed up the notion that both cancer and cancer therapy affect the platelet proteome. The aim of the current study was 1) to identify a pan-cancer proteome signature that could be used to discriminate patients with cancer from healthy individuals, and 2) to investigate the effect of cancer therapy on the platelet proteome. In this study, we included patients with cancer and healthy controls. Using global protein profiling by mass spectrometry-based proteomics we determined that the platelet proteome is affected by both cancer presence and antitumor therapy.
2021-09-08 | PXD010380 | Pride
Project description:Several members of SRSF family play wide-ranging roles in the regulation of transcription and post-splicing processes as well as splice sites selection. Although the expression of SRSF3 was reported to be overexpressed in several cancers, the roles of SRSF3 in the cancer cells are almost unknown. We analyzed differentially expressed genes in SRSF3 siRNA-treated HCT116 cells and identified the specific pathways regulated by SRSF3. After treatment of HCT116 cells with SRSF3 (sample 02) or control (sample 01) siRNA, total RNA was extracted using RNeasy Mini Kit (Qiagen, Valencia, CA). The quality of the purified RNA and its applicability for microarray analysis were assessed by the Agilent 2100 Bioanalyzer using a RNA 6000 Nano Labchip kit (Agilent Technologies, Palo Alto, CA, USA). Total RNA (400 ng) was used for amplification, labeling and hybridization to a whole human genome oligoDNA microarray (4x44k; Agilent) according to the manufacture’s instructions.
2013-08-04 | E-GEOD-31876 | biostudies-arrayexpress