Immune cells surveil aberrantly sialylated O-glycans on megakaryocytes to regulate platelet count
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA742044 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14932354.fastq.gz | Fastqsanger.gz | |||
| SRR14932355.fastq.gz | Fastqsanger.gz | |||
| SRR14932356.fastq.gz | Fastqsanger.gz | |||
| SRR14932357.fastq.gz | Fastqsanger.gz | |||
| SRR14932358.fastq.gz | Fastqsanger.gz |
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Project description:Immune thrombocytopenia (ITP) is a common platelet disorder in pediatric patients. Pediatric and adult ITP have been associated with sialic acid alterations, but the pathophysiology of ITP remains elusive, and ITP is often a diagnosis of exclusion. Our analysis of pediatric ITP plasma samples showed increased anti-Thomsen-Friedenreich antigen (TF-antigen) antibody representation, suggesting increased exposure of the typically sialylated and cryptic TF-antigen in these patients. The O-glycan sialyltransferase St3gal1 add sialic acid specifically on the TF-antigen. To understand if TF-antigen exposure associates with thrombocytopenia, we generated a mouse model with targeted deletion of St3gal1 in megakaryocytes (MK) (St3gal1MK-/-). TF-antigen exposure was restricted to MKs and resulted in thrombocytopenia. Deletion of Jak3 in St3gal1MK-/- mice normalized platelet counts implicating involvement of immune cells. Interferon-producing Siglec H-positive bone marrow (BM) immune cells engaged with O-glycan sialic acid moieties to regulate type I interferon (IFN-I) secretion and platelet release (thrombopoiesis), as evidenced by partially normalized platelet count following and inhibition of interferon and Siglec H receptors. Single cell RNAseq determined that TF-antigen exposure by MKs primed St3gal1MK-/- BM immune cells to release IFN-I. Single cell RNAseq further revealed a new population of immune cells with a plasmacytoid dendritic cell (pDC)-like signature and concomitant upregulation of immunoglobulin re-arrangement gene transcripts Igkc and Ighm, suggesting additional immune regulatory mechanisms. Thus, aberrant TF-antigen moieties, often found in pathological conditions, regulate immune cells and thrombopoiesis in the BM, leading to reduced platelet count.
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Project description:Srf is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. In order to test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F (KO) mice are born with normal mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased numbers and percentages of CD41+ megakaryocytes (WT: 0.41+/-0.06%; KO: 1.92+/-0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by both FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are downregulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production, due at least in part, to regulation of cytoskeletal genes. C-kit+CD41+ megakaryocyte progenitors from PF4-Cre/SRF C57BL/6 SRF WT (3) and C57BL/6 SRF KO (3) mice were sorted by flow cytometry and cultured for three days in thrombopoietin.
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Project description:Srf is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. In order to test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F (KO) mice are born with normal mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased numbers and percentages of CD41+ megakaryocytes (WT: 0.41+/-0.06%; KO: 1.92+/-0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by both FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are downregulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production, due at least in part, to regulation of cytoskeletal genes.
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