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Cytokine Nov 2021The blood vascular system of mammals is unique in nature; inhabited with a pool of tiny small cell fragments called platelets; attributed with the most important... (Review)
Review
The blood vascular system of mammals is unique in nature; inhabited with a pool of tiny small cell fragments called platelets; attributed with the most important patrolling tasks to check integrity of the entire endothelial landscape. Their production is tightly coupled with hematopoietic system where everything starts from self renewable multipotent hematopoietic stem cells (HSCs) which eventually undergo dual step (megakaryopoiesis-thrombopoiesis) thrombocytes production. Several cytokines tune the fate of every progenitor cells during hematopoiesis through temporal activation of specific transcription factors. Though platelets generated through steady state hematopoiesis are involved in the regulation of vascular homeostasis, these cells can sense pathogens through its innate immune sensors and can mount crucial responses against the invading pathogen. For this, the primary aim of many infections including Leishmania is to induce thrombocytopenia within infected host. But the underlying mechanism of this induced thrombocytopenia in Leishmania infection has not been evaluated. Elucidation of these mechanisms will be fruitful to design new chemotherapeutic strategies.
Topics: Animals; Cytokines; Hematopoietic Stem Cells; Humans; Immunity, Innate; Leishmaniasis; Thrombocytopenia; Thrombopoiesis
PubMed: 33127256
DOI: 10.1016/j.cyto.2020.155310 -
Biomeditsinskaia Khimiia Apr 2022In recent years, interest in the study of platelets, significantly increased due to recent discoveries providing convincing evidence that their functions by are not... (Review)
Review
In recent years, interest in the study of platelets, significantly increased due to recent discoveries providing convincing evidence that their functions by are not limited to their participation in the blood coagulation mechanism. Many works are devoted to the study of the functional state of platelets under conditions of acute and chronic alcohol exposure. The results of such studies can be useful for the development of new markers of the degree of alcohol intoxication of the body for the subsequent choice of the method drug correction of disorders caused by acute or chronic alcohol effects. The review summarizes results in vivo and in vitro of studies performed during more than 60 years on the effect of ethanol on the biogenesis, number, morphology and biochemistry of platelets.
Topics: Biology; Blood Platelets; Ethanol
PubMed: 35485482
DOI: 10.18097/PBMC20226802081 -
Blood Dec 2021Immune thrombocytopenia (ITP) is a platelet disorder. Pediatric and adult ITP have been associated with sialic acid alterations, but the pathophysiology of ITP remains...
Immune thrombocytopenia (ITP) is a platelet disorder. 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 adds 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 secretion and platelet release (thrombopoiesis), as evidenced by partially normalized platelet count following inhibition of interferon and Siglec H receptors. Single-cell RNA-sequencing determined that TF antigen exposure by MKs primed St3gal1MK-/- BM immune cells to release type I interferon. Single-cell RNA-sequencing further revealed a new population of immune cells with a plasmacytoid dendritic cell-like signature and concomitant upregulation of the immunoglobulin rearrangement 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.
Topics: Adolescent; Animals; Antigens, Tumor-Associated, Carbohydrate; Child; Child, Preschool; Humans; Infant; Megakaryocytes; Mice, Inbred C57BL; Platelet Count; Polysaccharides; Purpura, Thrombocytopenic, Idiopathic; Sialyltransferases; beta-Galactoside alpha-2,3-Sialyltransferase; Mice
PubMed: 34324649
DOI: 10.1182/blood.2020008238 -
Frontiers in Immunology 2022Megakaryocytes (MKs) are large cells giving rise to platelets. It is well established that in adults, MKs develop from hematopoietic stem cells and reside in the bone... (Review)
Review
Megakaryocytes (MKs) are large cells giving rise to platelets. It is well established that in adults, MKs develop from hematopoietic stem cells and reside in the bone marrow. MKs are also rare but normal constituents of the venous blood returning to the lungs, and MKs are found in the lung vasculature (MK), suggesting that these cells are migrants from the bone marrow and get trapped in lung capillaries where the final steps of platelet production can occur. An unprecedented increase in the number of lung and circulating MKs was described in coronavirus disease 2019 (COVID-19) patients, suggesting that lung thrombopoiesis may be increased during lung infection and/or thromboinflammation. In addition to the population of platelet-producing intravascular MKs in the lung, a population of lung-resident megakaryocytes (MK) has been identified and presents a specific immune signature compared to its bone marrow counterparts. Recent single-cell analysis and intravital imaging have helped us gain a better understanding of these populations in mouse and human. This review aims at summarizing the recent data on increased occurrence of lung MKs and discusses their origin, specificities, and potential role in homeostasis and inflammatory and infectious lung diseases. Here, we address remaining questions, controversies, and methodologic challenges for further studies of both MK and MK.
Topics: Humans; Mice; Animals; Megakaryocytes; Inflammation; COVID-19; Thrombosis; Lung
PubMed: 36524131
DOI: 10.3389/fimmu.2022.1029223 -
Proceedings of the National Academy of... Nov 2022Platelets play a role not only in hemostasis and thrombosis, but also in inflammation and innate immunity. We previously reported that an activated form of tyrosyl-tRNA...
Platelets play a role not only in hemostasis and thrombosis, but also in inflammation and innate immunity. We previously reported that an activated form of tyrosyl-tRNA synthetase (YRS) has an extratranslational activity that enhances megakaryopoiesis and platelet production in mice. Here, we report that YRS mimics inflammatory stress inducing a unique megakaryocyte (MK) population with stem cell (Sca1) and myeloid (F4/80) markers through a mechanism dependent on Toll-like receptor (TLR) activation and type I interferon (IFN-I) signaling. This mimicry of inflammatory stress by YRS was studied in mice infected by lymphocytic choriomeningitis virus (LCMV). Using Sca1/EGFP transgenic mice, we demonstrated that IFN-I induced by YRS or LCMV infection suppressed normal hematopoiesis while activating an alternative pathway of thrombopoiesis. Platelets of inflammatory origin (Sca1/EGFP) were a relevant proportion of those circulating during recovery from thrombocytopenia. Analysis of these "inflammatory" MKs and platelets suggested their origin in myeloid/MK-biased hematopoietic stem cells (HSCs) that bypassed the classical MK-erythroid progenitor (MEP) pathway to replenish platelets and promote recovery from thrombocytopenia. Notably, inflammatory platelets displayed enhanced agonist-induced activation and procoagulant activities. Moreover, myeloid/MK-biased progenitors and MKs were mobilized from the bone marrow, as evidenced by their presence in the lung microvasculature within fibrin-containing microthrombi. Our results define the function of YRS in platelet generation and contribute to elucidate platelet alterations in number and function during viral infection.
Topics: Mice; Animals; Thrombopoiesis; Tyrosine-tRNA Ligase; Thrombocytopenia; Virus Diseases; Thrombosis; Mice, Transgenic; Spinocerebellar Ataxias
PubMed: 36409883
DOI: 10.1073/pnas.2212659119 -
Cancer Chemotherapy and Pharmacology May 2022Lurbinectedin is an alkylating agent approved for the second-line treatment of small cell lung cancer. Although initial studies showed no association between body...
Lurbinectedin is an alkylating agent approved for the second-line treatment of small cell lung cancer. Although initial studies showed no association between body surface area (BSA) and drug clearance, the recommended dose is 3.2 mg/m every 3 weeks. This recommendation was based on an exposure-response study, which demonstrated that patients with lower BSA had a higher incidence of thrombocytopenia. Herein we present the factors associated with BSA and thrombopoiesis, which may have contributed to the observed relationship.
Topics: Anemia; Body Surface Area; Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Thrombocytopenia
PubMed: 35362793
DOI: 10.1007/s00280-022-04422-6 -
Blood Jun 2022Platelets (small, anucleate cell fragments) derive from large precursor cells, megakaryocytes (MKs), that reside in the bone marrow. MKs emerge from hematopoietic stem...
Platelets (small, anucleate cell fragments) derive from large precursor cells, megakaryocytes (MKs), that reside in the bone marrow. MKs emerge from hematopoietic stem cells in a complex differentiation process that involves cytoplasmic maturation, including the formation of the demarcation membrane system, and polyploidization. The main function of MKs is the generation of platelets, which predominantly occurs through the release of long, microtubule-rich proplatelets into vessel sinusoids. However, the idea of a 1-dimensional role of MKs as platelet precursors is currently being questioned because of advances in high-resolution microscopy and single-cell omics. On the one hand, recent findings suggest that proplatelet formation from bone marrow-derived MKs is not the only mechanism of platelet production, but that it may also occur through budding of the plasma membrane and in distant organs such as lung or liver. On the other hand, novel evidence suggests that MKs not only maintain physiological platelet levels but further contribute to bone marrow homeostasis through the release of extracellular vesicles or cytokines, such as transforming growth factor β1 or platelet factor 4. The notion of multitasking MKs was reinforced in recent studies by using single-cell RNA sequencing approaches on MKs derived from adult and fetal bone marrow and lungs, leading to the identification of different MK subsets that appeared to exhibit immunomodulatory or secretory roles. In the following article, novel insights into the mechanisms leading to proplatelet formation in vitro and in vivo will be reviewed and the hypothesis of MKs as immunoregulatory cells will be critically discussed.
Topics: Blood Platelets; Bone Marrow; Hematopoietic Stem Cells; Megakaryocytes; Thrombopoiesis
PubMed: 34582554
DOI: 10.1182/blood.2020009302 -
Journal of Thrombosis and Haemostasis :... Sep 2019The past decade has brought unprecedented advances in our understanding of megakaryocyte (MK) biology and platelet production, processes that are strongly dependent on... (Review)
Review
The past decade has brought unprecedented advances in our understanding of megakaryocyte (MK) biology and platelet production, processes that are strongly dependent on the cytoskeleton. Facilitated by technological innovations, such as new high-resolution imaging techniques (in vitro and in vivo) and lineage-specific gene knockout and reporter mouse strains, we are now able to visualize and characterize the molecular machinery required for MK development and proplatelet formation in live mice. Whole genome and RNA sequencing analysis of patients with rare platelet disorders, combined with targeted genetic interventions in mice, has led to the identification and characterization of numerous new genes important for MK development. Many of the genes important for proplatelet formation code for proteins that control cytoskeletal dynamics in cells, such as Rho GTPases and their downstream targets. In this review, we discuss how the final stages of MK development are controlled by the cellular cytoskeletons, and we compare changes in MK biology observed in patients and mice with mutations in cytoskeleton regulatory genes.
Topics: Actins; Animals; Blood Platelet Disorders; Blood Platelets; Blood Proteins; Cytoplasmic Granules; Cytoskeleton; Formins; Genes, Reporter; Humans; Mice; Mice, Knockout; Nonmuscle Myosin Type IIA; Organelle Biogenesis; Thrombopoiesis; Tubulin
PubMed: 31220402
DOI: 10.1111/jth.14544 -
Platelets Jul 2020Electron microscopy (EM) has a long history in megakaryocyte (MK) cellular biology. This chapter shows how the electron microscope, since its first appearance almost... (Review)
Review
Electron microscopy (EM) has a long history in megakaryocyte (MK) cellular biology. This chapter shows how the electron microscope, since its first appearance almost 90 years ago, has occupied center stage in the studies of MK morphology and function. It describes some of the more productive EM techniques that have shaped our understanding of the physiology of thrombopoiesis. These include the standard transmission and scanning EM techniques as well as the new imaging methods, correlative microscopy and volume EM which provide information on the 3D organization of MKs on different scales: single organelles, whole cells and tissues. For each technique, we list the advantages and limitations, the resolution that can be achieved, the technical difficulties and the applications in MK biology.
Topics: Humans; Megakaryocytes; Microscopy, Electron, Scanning
PubMed: 31903825
DOI: 10.1080/09537104.2019.1708885