Plasmacytoid dendritic cells regulate megakaryocyte and platelet homeostasis in steady state and disease
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PROVIDER: PRJNA769266 | ENA |
REPOSITORIES: ENA
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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:Platelet homeostasis is essential for vascular integrity and immune defense. While the process of platelet formation by fragmenting megakaryocytes (thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of megakaryocytes (MKs) by their progenitor cells (megakaryopoiesis) remains unclear. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFN- to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for MK and platelet homeostasis in steady state and stress. However, excessive activation of pDCs, such as by viral infections, can disturb this homeostatic circuit. Accordingly, we show that pDCs activated by SARS-CoV2 drive inappropriate megakaryopoiesis. Together, we uncover a hitherto unknown pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain tissue homeostasis of the megakaryocytic lineage.
2024-05-01 | GSE261996 | GEO
Project description:Expression of the RNA-binding protein is increased upon megakaryocyte commitment, and may coordinate with mRNA stability and translation during megakaryopoiesis. Reduced expression of ATXN2 in human megakaryocytic cells decreased protein synthesis and total protein content despite equal mRNA expression. Genome-wide comparision of subpolysomal versus polysomal mRNA showed that both protein synthesis and protein degradation are derailed in absence of ATXN2. Furthermore, ATXN2 was associated with PABP and DDX6, proteins that control mRNA stability through the polyA-tail. These findings indicate that ATXN2 is involved in protein metabolism in megakaryocytes and platelet function.
2014-12-31 | GSE63297 | GEO
Project description:Sp1 and Sp3 belong to the Specificity proteins (Sp)/Krüppel-like transcription factor family. They are closely related, ubiquitously expressed and recognize G-rich DNA motifs. They are thought to regulate generic processes such as cell cycle and growth control, metabolic pathways and apoptosis. Ablation of Sp1 or Sp3 in mice is lethal, and combined haploinsufficiency results in hematopoietic defects during the fetal stages. Here, we show that in adult mice conditional ablation of either Sp1 or Sp3 has minimal impact on hematopoiesis, while the simultaneous loss of Sp1 and Sp3 results in severe macrothrombocytopenia and platelet dysfunction. We employed flow cytometry, cell culture and electron microscopy and show that although megakaryocyte numbers are normal in bone marrow and spleen, they display a less compact demarcation membrane system and a striking inability to form proplatelets. Through megakaryocyte transcriptomics and platelet proteomics we identified several cytoskeleton-related proteins and downstream effector kinases, including Mylk, that were downregulated upon Sp1/Sp3 depletion, providing an explanation for the observed defects in megakaryopoiesis. We show that Mylk is required for proplatelet formation and stabilization and for ITAM-receptor mediated platelet aggregation. Our data highlights the specific vs generic role of these ubiquitous transcription factors in the highly specialized megakaryocytic lineage. Megakaryocyte mRNA profiles of Sp1fl/fl::Sp3fl/fl (WTlox) and Pf4-Cre::Sp1fl/fl::Sp3fl/fl (dKO) mice were generated by deep sequencing, in triplicate.
2014-12-18 | E-GEOD-58707 | biostudies-arrayexpress
Project description:Sp1 and Sp3 belong to the Specificity proteins (Sp)/Krüppel-like transcription factor family. They are closely related, ubiquitously expressed and recognize G-rich DNA motifs. They are thought to regulate generic processes such as cell cycle and growth control, metabolic pathways and apoptosis. Ablation of Sp1 or Sp3 in mice is lethal, and combined haploinsufficiency results in hematopoietic defects during the fetal stages. Here, we show that in adult mice conditional ablation of either Sp1 or Sp3 has minimal impact on hematopoiesis, while the simultaneous loss of Sp1 and Sp3 results in severe macrothrombocytopenia and platelet dysfunction. We employed flow cytometry, cell culture and electron microscopy and show that although megakaryocyte numbers are normal in bone marrow and spleen, they display a less compact demarcation membrane system and a striking inability to form proplatelets. Through megakaryocyte transcriptomics and platelet proteomics we identified several cytoskeleton-related proteins and downstream effector kinases, including Mylk, that were downregulated upon Sp1/Sp3 depletion, providing an explanation for the observed defects in megakaryopoiesis. We show that Mylk is required for proplatelet formation and stabilization and for ITAM-receptor mediated platelet aggregation. Our data highlights the specific vs generic role of these ubiquitous transcription factors in the highly specialized megakaryocytic lineage.
2014-12-18 | GSE58707 | GEO
Project description:Hematopoiesis generates cell diversity through evolutionarily-determined differentiation programs defined at steady-state conditions. Here, we show that peripheral innate immune activation can generate cell diversity and functional specialization during the activation process. We found that activation of steady state human plasmacytoid pre-dendritic cells (pDCs) with a single microbial stimulus induced their differentiation into three phenotypically, morphologically, and functionally distinct subsets, in the absence of cell division: P1 (PD-L1+CD80-), P2 (PD-L1+CD80+) and P3 (PD-L1-CD80+). Different stimuli induced variable proportions of the subsets, suggesting that steady state pDC are multipotent. P1-pDCs display a plasmacytoid morphology and strong specialization on IFN production, whereas P3-pDCs adopt a dendritic morphology and adaptive immune functions. P2-pDCs have an intermediate functional profile. We found that a P1-pDC phenotype is present in human autoimmune diseases associated to type I IFN production as lupus and psoriasis, supporting their pathophysiological relevance. We propose that peripheral innate activation represents a differentiation mechanism to generate subsets diversity and functional complementarity in human pDCs.
2017-12-04 | GSE84204 | GEO
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:Plasmacytoid dendritic cells regulate tissue homeostasis of megakaryocytes
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Project description:Advances in platelet transcriptomics allow prediction of the full human platelet proteome. We integrated proteomes from six cohorts, encompassing 5.2k unique proteins (3.5k with copy numbers), with novel genome-wide platelet and megakaryocyte transcriptomes (Blueprint).
2021-09-09 | PXD022011 | Pride
Project description:Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We examined if non-viral sepsis induces differential platelet gene expression and reactivity. Non-viral sepsis significantly upregulated IFITM3, an interferon responsive gene that restricts viral replication
2022-12-01 | GSE210797 | GEO