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Critical Reviews in Oncology/hematology Mar 2008Megakaryocytopoiesis is a continuous developmental process of platelet production. In this process, a complex network of hemopoietic growth factors are involved, among... (Review)
Review
Megakaryocytopoiesis is a continuous developmental process of platelet production. In this process, a complex network of hemopoietic growth factors are involved, among which TPO (thrombopoietin) is the most thoroughly investigated regulator of MKs (megakaryocytes). In addition to TPO, other regulators also have non-negligible effects on megakaryocytopoiesis. The majority of their effects are independent of TPO signaling. To date, TPO-independent megakaryocytopoiesis forms a regulatory system that includes four signals and (an) unknown signaling pathway(s). These four pathways are the gp 130 (glycoprotein 130)-dependent signaling pathway, the Notch pathway, NMDA (N-methyl-d-aspartate) receptor-mediated signaling, and the SDF-1 (stromal cell-derived factor-1)/FGF-4 (fibroblast growth factor-4) paradigm. Understanding of the TPO-independent regulatory system is important because the system may offer additional opportunities to understand the developmental process and the mechanisms of disorders characterized by abnormal MK and platelet production, such as thrombocytopenia and thrombocythemia, and to advance the development of therapeutics.
Topics: Animals; Chemokine CXCL12; Cytokine Receptor gp130; Fibroblast Growth Factor 4; Humans; Receptors, N-Methyl-D-Aspartate; Receptors, Notch; Signal Transduction; Thrombopoiesis; Thrombopoietin
PubMed: 18093840
DOI: 10.1016/j.critrevonc.2007.11.003 -
[Exploring the mysteries of megakaryocytopoiesis and thrombopoiesis through comparative hematology].[Rinsho Ketsueki] the Japanese Journal... 2019In modern hematology, research on hematopoiesis and blood cells in vertebrates, such as birds, reptiles, amphibians, and fish, is lagging. This is because there are many... (Review)
Review
In modern hematology, research on hematopoiesis and blood cells in vertebrates, such as birds, reptiles, amphibians, and fish, is lagging. This is because there are many experimental constraints when selecting subjects other than humans and mice as research subjects. Currently, the availability of flow cytometry to count classified nucleated blood cells and utilization of whole genome information have led to novel findings. For example, in case of amphibian hematopoiesis studies, megakaryocytes have been found to be present in African clawed frogs (Xenopus laevis), which do not have platelets but have circulating nucleated thrombocytes. Moreover, we shed light on several mysteries, such as the C-terminal region in human TPO molecules not being found in birds, amphibians, and fish TPO molecules and the functional universalities of mutant CALR-MPL binding and EPO-EphB4 binding, in conjunction with comparative hematology.
Topics: Animals; Blood Platelets; Genome; Hematology; Histology, Comparative; Humans; Megakaryocytes; Mice; Thrombopoiesis; Vertebrates
PubMed: 31597828
DOI: 10.11406/rinketsu.60.1063 -
British Journal of Haematology Nov 2011Megakaryocytopoiesis is governed by a complex network of haematopoietic growth factors that regulate the different stages of the process, in which haematopoietic stem... (Review)
Review
Megakaryocytopoiesis is governed by a complex network of haematopoietic growth factors that regulate the different stages of the process, in which haematopoietic stem cells undergo megakaryocytic lineage commitment, proliferation, maturation, and functional activation to produce platelets. MicroRNAs (miRNA) are a class of about 22-nucleotide noncoding RNAs that have been highly conserved during evolution and play a significant role in haematopoiesis, including differentiation and lineage commitment of megakaryocyte. This review summarizes the miRNAs which have changed expression during megakaryocytopoiesis, and their positive and negative functions on megakaryocytic differentiation. In addition, the abnormal miRNA expression profiles in megakaryocytic disorders are reviewed.
Topics: Animals; Gene Expression Regulation; Humans; Megakaryocytes; MicroRNAs; Thrombopoiesis
PubMed: 21910717
DOI: 10.1111/j.1365-2141.2011.08859.x -
Platelets Dec 2023Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot encode proteins, and a better understanding of the complex interaction networks coordinated by ncRNAs... (Review)
Review
Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot encode proteins, and a better understanding of the complex interaction networks coordinated by ncRNAs will provide a theoretical basis for the development of therapeutics targeting the regulatory effects of ncRNAs. Platelets are produced upon the differentiation of hematopoietic stem cells into megakaryocytes, 10 per day, and are renewed every 8-9 days. The process of thrombopoiesis is affected by multiple factors, in which ncRNAs also exert a significant regulatory role. This article reviewed the regulatory roles of ncRNAs, mainly microRNAs (miRNAs), circRNAs (circular RNAs), and long non-coding RNAs (lncRNAs), in thrombopoiesis in recent years as well as their roles in primary immune thrombocytopenia (ITP).
Topics: Humans; Thrombopoiesis; Blood Platelets; Megakaryocytes; MicroRNAs; RNA, Untranslated
PubMed: 36550091
DOI: 10.1080/09537104.2022.2157382 -
Cell Stem Cell Mar 2021Despite our growing understanding of embryonic immune development, rare early megakaryocytes (MKs) remain relatively understudied. Here we used single-cell RNA...
Despite our growing understanding of embryonic immune development, rare early megakaryocytes (MKs) remain relatively understudied. Here we used single-cell RNA sequencing of human MKs from embryonic yolk sac (YS) and fetal liver (FL) to characterize the transcriptome, cellular heterogeneity, and developmental trajectories of early megakaryopoiesis. In the YS and FL, we found heterogeneous MK subpopulations with distinct developmental routes and patterns of gene expression that could reflect early functional specialization. Intriguingly, we identified a subpopulation of CD42bCD14 MKs in vivo that exhibit high expression of genes associated with immune responses and can also be derived from human embryonic stem cells (hESCs) in vitro. Furthermore, we identified THBS1 as an early marker for MK-biased embryonic endothelial cells. Overall, we provide important insights and invaluable resources for dissection of the molecular and cellular programs underlying early human megakaryopoiesis.
Topics: Cell Differentiation; Endothelial Cells; Human Embryonic Stem Cells; Humans; Megakaryocytes; Thrombopoiesis
PubMed: 33340451
DOI: 10.1016/j.stem.2020.11.006 -
British Journal of Haematology Jun 2013Megakaryocytopoiesis involves the commitment of haematopoietic stem cells, proliferation and terminal differentiation of megakaryocytic progenitors (MK-p) and maturation... (Review)
Review
Megakaryocytopoiesis involves the commitment of haematopoietic stem cells, proliferation and terminal differentiation of megakaryocytic progenitors (MK-p) and maturation of megakaryocytes (MKs) to produce functional platelets. This complex process occurs in specialized niches in the bone marrow where MKs align adjacent to vascular endothelial cells, form proplatelet projections and release platelets into the circulation. Thrombopoietin (THPO, TPO) is the primary growth factor for the MK lineage and necessary at all stages of development. THPO is constitutively produced in the liver, and binds to MPL (c-Mpl) receptor on platelets and MKs. This activates a cascade of signalling molecules, which induce transcription factors to drive MK development and thrombopoiesis. Decreased turnover rate and platelet number result in increased levels of free THPO, which induces a concentration-dependent compensatory response of marrow-MKs to enhance platelet production. Newly developed thrombopoietic agents operating via MPL receptor facilitate platelet production in thrombocytopenic states, primarily immune thrombocytopenia. Other drugs are available for attenuating malignant thrombocytosis. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease states, and the innovative drugs and therapeutic modalities to stimulate or decrease thrombopoiesis.
Topics: Animals; Blood Platelets; Bone Marrow; Cell Differentiation; Cellular Microenvironment; Clinical Trials as Topic; Homeostasis; Humans; Janus Kinases; Megakaryocytes; Molecular Mimicry; Protein Kinase Inhibitors; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thrombocytopenia; Thrombocytosis; Thrombopoiesis; Thrombopoietin
PubMed: 23594368
DOI: 10.1111/bjh.12328 -
Platelets Aug 2020
Topics: Animals; Blood Platelets; Disease Susceptibility; Humans; Megakaryocytes; Thrombopoiesis
PubMed: 32697612
DOI: 10.1080/09537104.2020.1773129 -
Immunity Dec 2022Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that...
Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events.
Topics: Humans; Megakaryocytes; Thrombopoiesis; Neutrophils; Cardiovascular Diseases; Blood Platelets; Thrombosis; Myocardial Infarction
PubMed: 36272416
DOI: 10.1016/j.immuni.2022.10.001 -
Journal of Thrombosis and Haemostasis :... Jul 2009Type 2B von Willebrand disease (VWD2B) is caused by gain-of-function amino acid substitutions in the von Willebrand factor (VWF) A1 domain. These allow facilitated... (Review)
Review
Type 2B von Willebrand disease (VWD2B) is caused by gain-of-function amino acid substitutions in the von Willebrand factor (VWF) A1 domain. These allow facilitated binding of mutated VWF to platelet GPIbalpha with prolonged lifetimes of VWF bonds and enhanced ADAMTS-13 cleavage of large VWF multimers. A bleeding rather than prothrombotic syndrome is due to: (i) decreased large VWF multimers in plasma; (ii) limited thrombus formation; and (iii) thrombocytopenia affecting some but not all patients. Accumulating evidence points to an altered megakaryocytopoiesis in VWD2B with the production of enlarged or giant platelets showing an abnormal ultrastructure and, in a cohort of patients, the presence of circulating platelet agglutinates. In fact, evidence from in vitro cultures and marrow aspirates suggests that the upregulated VWF function can lead to abnormal VWF trafficking in megakaryocytes, a modified platelet production with interacting proplatelets, and the presence or even release of platelet agglutinates in the bone marrow.
Topics: Humans; Megakaryocytes; Platelet Adhesiveness; Thrombopoiesis; von Willebrand Diseases; von Willebrand Factor
PubMed: 19630816
DOI: 10.1111/j.1538-7836.2009.03371.x -
Blood Jul 1965
Topics: Blood Cell Count; Blood Platelets; Cell Division; DNA; Hematopoiesis; Megakaryocytes; Rats; Research; Thrombopoiesis; Thymidine; Tritium
PubMed: 14314398
DOI: No ID Found