-
Cells Apr 2020The biomechanical properties of the bone marrow microenvironment emerge from a combination of interactions between various extracellular matrix (ECM) structural proteins... (Review)
Review
The biomechanical properties of the bone marrow microenvironment emerge from a combination of interactions between various extracellular matrix (ECM) structural proteins and soluble factors. Matrix stiffness directs stem cell fate, and both bone marrow stromal and hematopoietic cells respond to biophysical cues. Within the bone marrow, the megakaryoblasts and erythroblasts are thought to originate from a common progenitor, giving rise to fully mature magakaryocytes (the platelet precursors) and erythrocytes. Erythroid and megakaryocytic progenitors sense and respond to the ECM through cell surface adhesion receptors such as integrins and mechanosensitive ion channels. While hematopoietic stem progenitor cells remain quiescent on stiffer ECM substrates, the maturation of the erythroid and megakaryocytic lineages occurs on softer ECM substrates. This review surveys the major matrix structural proteins that contribute to the overall biomechanical tone of the bone marrow, as well as key integrins and mechanosensitive ion channels identified as ECM sensors in context of megakaryocytosis or erythropoiesis.
Topics: Cell Differentiation; Cell Lineage; Erythroid Cells; Extracellular Matrix; Humans; Megakaryocytes
PubMed: 32268541
DOI: 10.3390/cells9040894 -
British Journal of Haematology Apr 2014
Topics: Blood Platelets; Humans; Megakaryocytes; Thrombopoiesis
PubMed: 24690043
DOI: 10.1111/bjh.12799 -
The Journal of Clinical Investigation Dec 2005Platelets, derived from megakaryocytes, have an essential role in thrombosis and hemostasis. Over the past 10 years, a great deal of new information has been obtained... (Review)
Review
Platelets, derived from megakaryocytes, have an essential role in thrombosis and hemostasis. Over the past 10 years, a great deal of new information has been obtained concerning the various aspects of hematopoiesis necessary to maintain a steady-state platelet level to support physiologic hemostasis. Here we discuss the differentiation of HSCs into megakaryocytes, with emphasis on the key cytokine signaling pathways and hematopoietic transcription factors. Recent insight into these processes elucidates the molecular bases of numerous acquired and inherited hematologic disorders. It is anticipated that the growing knowledge in these areas may be exploited for new therapeutic strategies to modulate both platelet numbers and their thrombogenicity.
Topics: Animals; Blood Platelet Disorders; Cell Differentiation; Cell Lineage; Cytokines; Hematopoiesis; Humans; Megakaryocytes; Models, Biological; Platelet Count; Signal Transduction; Thrombopoietin; Transcription Factors
PubMed: 16322777
DOI: 10.1172/JCI26720 -
Journal of Thrombosis and Haemostasis :... Jul 2009Each day in every human, approximately 1 x 10(11) platelets are produced by the cytoplasmic fragmentation of megakaryocytes (MK), their marrow precursor cells. Platelets... (Review)
Review
Each day in every human, approximately 1 x 10(11) platelets are produced by the cytoplasmic fragmentation of megakaryocytes (MK), their marrow precursor cells. Platelets are the predominating factor in the process of hemostasis and thrombosis. Recent studies have shown that platelets also play a hitherto unsuspected role in several other processes such as inflammation, innate immunity, neoangiogenesis and tumor metastasis. The late phases of MK differentiation identified by polyploidization, maturation and organized fragmentation of the cytoplasm leading to the release of platelets in the blood stream represent a unique model of differentiation. The molecular and cellular mechanisms regulating platelet biogenesis are better understood and may explain several platelet disorders. This review focuses on MK polyploidization, and platelet formation, and discusses their alteration in some platelet disorders.
Topics: Blood Platelet Disorders; Blood Platelets; Cell Differentiation; Humans; Megakaryocytes; Polyploidy
PubMed: 19630806
DOI: 10.1111/j.1538-7836.2009.03398.x -
Blood Feb 2008The study of thrombopoiesis has evolved greatly since an era when platelets were termed "the dust of the blood," only about 100 years ago. During this time... (Review)
Review
The study of thrombopoiesis has evolved greatly since an era when platelets were termed "the dust of the blood," only about 100 years ago. During this time megakaryocytes were identified as the origin of blood platelets; marrow-derived megakaryocytic progenitor cells were functionally defined and then purified; and the primary regulator of the process, thrombopoietin, was cloned and characterized and therapeutic thrombopoietic agents developed. During this journey we continue to learn that the physiologic mechanisms that drive proplatelet formation can be recapitulated in cell-free systems and their biochemistry evaluated; the molecular underpinnings of endomitosis are being increasingly understood; the intracellular signals sent by engagement of a large number of megakaryocyte surface receptors have been defined; and many of the transcription factors that drive megakaryocytic fate determination have been identified and experimentally manipulated. While some of these biologic processes mimic those seen in other cell types, megakaryocytes and platelets possess enough unique developmental features that we are virtually assured that continued study of thrombopoiesis will yield innumerable clinical and scientific insights for many decades to come.
Topics: Animals; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Megakaryocytes; Protein Biosynthesis; Thrombocytopenia; Thrombopoiesis
PubMed: 18223171
DOI: 10.1182/blood-2007-05-088500 -
Platelets Sep 2016The study of patients with inherited bleeding problems is a powerful approach in determining the function and regulation of important proteins in human platelets and... (Review)
Review
The study of patients with inherited bleeding problems is a powerful approach in determining the function and regulation of important proteins in human platelets and their precursor, the megakaryocyte. The normal range of platelet counts in the bloodstream ranges from 150 000 to 400 000 platelets per microliter and is normally maintained within a narrow range for each individual. This requires a constant balance between thrombopoiesis, which is primarily controlled by the cytokine thrombopoietin (TPO), and platelet senescence and consumption. Thrombocytopenia can be defined as a platelet count of less than 150 000 per microliter and can be acquired or inherited. Heritable forms of thrombocytopenia are caused by mutations in genes involved in megakaryocyte differentiation, platelet production and platelet removal. In this review, we will discuss the main causative genes known for inherited thrombocytopenia and highlight their diverse functions and whether these give clues on the processes of platelet production, platelet function and platelet lifespan. Additionally, we will highlight the recent advances in novel genes identified for inherited thrombocytopenia and their suggested function.
Topics: Animals; Apoptosis; Blood Platelets; Cell Differentiation; Cellular Senescence; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Megakaryocytes; Mutation; Thrombocytopenia; Thrombopoiesis
PubMed: 27025194
DOI: 10.3109/09537104.2016.1148806 -
Blood Jul 2011Erythroid cells and megakaryocytes are derived from a common precursor, the megakaryocyte-erythroid progenitor. Although these 2 closely related hematopoietic cell types... (Review)
Review
Erythroid cells and megakaryocytes are derived from a common precursor, the megakaryocyte-erythroid progenitor. Although these 2 closely related hematopoietic cell types share many transcription factors, there are several key differences in their regulatory networks that lead to differential gene expression downstream of the megakaryocyte-erythroid progenitor. With the advent of next-generation sequencing and our ability to precisely define transcription factor chromatin occupancy in vivo on a global scale, we are much closer to understanding how these 2 lineages are specified and in general how transcription factor complexes govern hematopoiesis.
Topics: Animals; Cell Differentiation; Cell Lineage; Erythroid Cells; Gene Regulatory Networks; Hematopoiesis; Humans; Megakaryocyte-Erythroid Progenitor Cells; Megakaryocytes; Models, Biological; Transcription Factors
PubMed: 21622645
DOI: 10.1182/blood-2011-04-285981 -
Military Medical Research Dec 2023The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of...
BACKGROUND
The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive.
METHODS
A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors.
RESULTS
In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-β (IFN-β) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR.
CONCLUSIONS
Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.
Topics: Humans; Animals; Mice; Megakaryocytes; Thrombocytopenia; Radiation Injuries; Apoptosis; Nucleotidyltransferases; Thrombosis
PubMed: 38111039
DOI: 10.1186/s40779-023-00499-z -
Cell Cycle (Georgetown, Tex.) 2014
Topics: Animals; Calpain; Cell Transformation, Neoplastic; GATA1 Transcription Factor; Humans; Leukemia; Megakaryocytes; Mutation; Positive Transcriptional Elongation Factor B; Ribonucleoproteins, Small Nuclear
PubMed: 24866976
DOI: 10.4161/cc.29324 -
Journal of Clinical and Experimental... 2018In 2017, the revised World Health Organization was published. Regarding myeloproliferative neoplasms, histological findings of bone marrow biopsy is becoming more... (Review)
Review
In 2017, the revised World Health Organization was published. Regarding myeloproliferative neoplasms, histological findings of bone marrow biopsy is becoming more important for diagnosis. This article highlights particularly the morphology of megakaryocytes and evaluation of myelofibrosis for pathological diagnosis, and immunohistochemistry which can detect somatic mutation.
Topics: Biopsy; Bone Marrow; Histological Techniques; Humans; Megakaryocytes; Primary Myelofibrosis
PubMed: 29998975
DOI: 10.3960/jslrt.18006