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Blood Jan 2024Megakaryocytes (MKs) generate thousands of platelets over their lifespan. The roles of platelets in infection and inflammation has guided an interest to the study of...
Megakaryocytes (MKs) generate thousands of platelets over their lifespan. The roles of platelets in infection and inflammation has guided an interest to the study of extramedullary thrombopoiesis and therefore MKs have been increasingly reported within the spleen and lung. However, the relative abundance of MKs in these organs compared to the bone marrow and the scale of their contribution to the platelet pool in a steady state remain controversial. We investigated the relative abundance of MKs in the adult murine bone marrow, spleen, and lung using whole-mount light-sheet and quantitative histological imaging, flow cytometry, intravital imaging, and an assessment of single-cell RNA sequencing (scRNA-seq) repositories. Flow cytometry revealed significantly higher numbers of hematopoietic stem and progenitor cells and MKs in the murine bone marrow than in spleens or perfused lungs. Two-photon intravital and light-sheet microscopy, as well as quantitative histological imaging, confirmed these findings. Moreover, ex vivo cultured MKs from the bone marrow subjected to static or microfluidic platelet production assays had a higher capacity for proplatelet formation than MKs from other organs. Analysis of previously published murine and human scRNA-seq data sets revealed that only a marginal fraction of MK-like cells can be found within the lung and most likely only marginally contribute to platelet production in the steady state.
Topics: Mice; Humans; Animals; Bone Marrow; Thrombopoiesis; Blood Platelets; Megakaryocytes; Spleen
PubMed: 37879046
DOI: 10.1182/blood.2023020895 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Apr 20065-hydroxtryptamine (5-HT, serotonin) has been recognized not only as a neurotransmitter and vasoactive agent, but also as a growth factor. 5-HT mainly binds to 5-HT(2)... (Review)
Review
5-hydroxtryptamine (5-HT, serotonin) has been recognized not only as a neurotransmitter and vasoactive agent, but also as a growth factor. 5-HT mainly binds to 5-HT(2) receptors or 5-HT(1) receptors on cell surface to stimulate cell proliferation through Ras or MAPK pathway in many cell types. It has been reported that 5-HT stimulates megakaryocytopoiesis via 5-HT receptors. The possible mechanism of 5-HT on the proliferation and differentiation of megakaryocytes (MK) has been discussed in this review article. In early stage of megakaryocytopoiesis, 5-HT may bind to 5-HT(2B) receptor on megakaryocytes, and promotes their proliferation and differentiation. In the late stage, 5-HT may involve in the platelet release procedure by inducing nitric oxide (NO) synthesis via 5-HT(2A) receptors. 5-HT can also antagonize the apoptotic effect induced by thrombospondin-1 (TSP-1) which is a platelet alpha granule protein and has synergic effect with platelet-derived growth factor (PDGF) to enhance megakaryocytes proliferation. Therefore, 5-HT is likely to be an important substance in the feedback regulation of thrombopoiesis. In this review the 5-HT and its receptors, 5-HT as cell growth factor, pathway of 5-HT stimulating cell proliferation and influance of 5-HT on MK-progenitor cells were summarized.
Topics: Humans; Megakaryocytes; Receptors, Serotonin; Receptors, Serotonin, 5-HT2; Serotonin; Thrombopoiesis; Thrombopoietin
PubMed: 16638226
DOI: No ID Found -
Blood Jan 2023
Topics: Humans; Glycosylation; Thrombopoiesis; Mutation; Thrombocytopenia
PubMed: 36701170
DOI: 10.1182/blood.2022019021 -
Internal Medicine (Tokyo, Japan) Aug 2003
Topics: Blood Platelets; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Thrombocytosis; Thrombopoiesis; Thrombopoietin
PubMed: 12924482
DOI: 10.2169/internalmedicine.42.632 -
Experimental Hematology Jan 2018In mammals, platelets are produced in the blood by cytoplasmic fragmentation of megakaryocytes (MKs). Platelet production is thus dependent on both the MK number and... (Review)
Review
In mammals, platelets are produced in the blood by cytoplasmic fragmentation of megakaryocytes (MKs). Platelet production is thus dependent on both the MK number and size. During differentiation, MKs switch from a division by mitosis to polyploidization by endomitosis to increase their size. The endomitotic process includes several successive rounds of DNA replication with an entry in mitosis with a failure in late cytokinesis and a defect in karyokinesis. This leads to a giant cell with a modal ploidy at 16N and one multilobulated nucleus. The entire genome is duplicated several times and all alleles remain functional producing a hypermetabolic cell. A defect in abscission explains the cytokinesis failure and is related to an altered accumulation of actomyosin at the cleavage furrow as a consequence of both a low local RhoA activity and silencing of the MYH10 gene. This mechanism is regulated by transcription factors that govern differentiation explaining the intricacies of both processes. However, the endomitotic cell cycle regulation is still incompletely understood, particularly mitosis entry, escape to the tetraploid checkpoint, and defect in karyokinesis. Polyploidization is regulated during ontogeny, the first embryonic MKs being 2N. The molecular mechanism of this embryo-fetal/adult transition is beginning to be understood. In physiological conditions, MK ploidy is increased by an enhanced platelet demand through the thrombopoietin/myeloproliferative leukemia axis. In numerous hematologic malignancies, MK ploidy decreases, but it is always associated with a defect in MK differentiation. It has been proposed that polyploidization induction could be a treatment for some malignant MK disorders.
Topics: Animals; Cell Cycle Checkpoints; Cell Cycle Proteins; Cytokinesis; DNA Replication; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Hematologic Neoplasms; Humans; Intercellular Signaling Peptides and Proteins; Mammals; Megakaryocytes; Mitosis; Molecular Targeted Therapy; Myelodysplastic Syndromes; Polyploidy; Signal Transduction; Thrombopoiesis; Thrombopoietin; Transcription Factors; rhoA GTP-Binding Protein
PubMed: 29111429
DOI: 10.1016/j.exphem.2017.10.001 -
Scientific Reports Jul 2017Megakaryocytopoiesis is a complex differentiation process driven by the hormone thrombopoietin by which haematopoietic progenitor cells give rise to megakaryocytes, the...
Megakaryocytopoiesis is a complex differentiation process driven by the hormone thrombopoietin by which haematopoietic progenitor cells give rise to megakaryocytes, the giant bone marrow cells that in turn break down to form blood platelets. The Tribbles Pseudokinase 3 gene (TRIB3) encodes a pleiotropic protein increasingly implicated in the regulation of cellular differentiation programmes. Previous studies have hinted that TRIB3 could be also involved in megakaryocytopoiesis but its role in this process has so far not been investigated. Using cellular model systems of haematopoietic lineage differentiation here we demonstrate that TRIB3 is a negative modulator of megakaryocytopoiesis. We found that in primary cultures derived from human haematopoietic progenitor cells, thrombopoietin-induced megakaryocytic differentiation led to a time and dose-dependent decrease in TRIB3 mRNA levels. In the haematopoietic cell line UT7/mpl, silencing of TRIB3 increased basal and thrombopoietin-stimulated megakaryocyte antigen expression, as well as basal levels of ERK1/2 phosphorylation. In primary haematopoietic cell cultures, silencing of TRIB3 facilitated megakaryocyte differentiation. In contrast, over-expression of TRIB3 in these cells inhibited the differentiation process. The in-vitro identification of TRIB3 as a negative regulator of megakaryocytopoiesis suggests that in-vivo this gene could be important for the regulation of platelet production.
Topics: Cell Cycle Proteins; Cell Differentiation; Cell Line; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Gene Silencing; Humans; Megakaryocytes; Phosphorylation; Protein Serine-Threonine Kinases; RNA, Messenger; Repressor Proteins; Thrombopoiesis; Thrombopoietin
PubMed: 28751721
DOI: 10.1038/s41598-017-07096-w -
Life Sciences Jul 2022Megakaryocytes (MKs) are typical cellular components in the circulating blood flowing from the heart into the lungs. Physiologically, MKs function as an important... (Review)
Review
Megakaryocytes (MKs) are typical cellular components in the circulating blood flowing from the heart into the lungs. Physiologically, MKs function as an important regulator of platelet production and immunoregulation. However, dysfunction in MKs is considered a trigger in various diseases. It has been described that the lung is an important site of platelet biogenesis from extramedullary MKs, which may play an essential role in various pulmonary diseases. With detailed studies, there are different degrees of numerical changes of MKs in coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis (PF), and other pulmonary diseases. Also, MKs inhibit or promote the development of pulmonary diseases through various pathways. Here, we summarize the current knowledge of MKs in pulmonary diseases, highlighting the physiological functions and integrated molecular mechanisms. We aim to shine new light on not only the subsequent study of MKs but also the diagnosis and treatment of pulmonary diseases.
Topics: Blood Platelets; COVID-19; Humans; Lung; Megakaryocytes; Respiratory Distress Syndrome; Thrombopoiesis
PubMed: 35508253
DOI: 10.1016/j.lfs.2022.120602 -
Arteriosclerosis, Thrombosis, and... Nov 2021Myeloproliferative neoplasms (MPNs) are a group of malignant disorders of the bone marrow where a dysregulated balance between proliferation and differentiation gives... (Review)
Review
Myeloproliferative neoplasms (MPNs) are a group of malignant disorders of the bone marrow where a dysregulated balance between proliferation and differentiation gives rise to abnormal numbers of mature blood cells. MPNs encompass a spectrum of disease entities with progressively more severe clinical features, including complications with thrombosis and hemostasis and an increased propensity for transformation to acute myeloid leukemia. There is an unmet clinical need for markers of disease progression. Our understanding of the precise mechanisms that influence pathogenesis and disease progression has been limited by access to disease-specific cells as biosources. Here, we review the landscape of MPN pathology and present blood platelets as potential candidates for disease-specific understanding. We conclude with our recent work discovering progressive platelet heterogeneity by subtype in a large clinical cohort of patients with MPN.
Topics: Animals; Antineoplastic Agents; Blood Coagulation; Blood Platelets; Humans; Molecular Targeted Therapy; Myeloproliferative Disorders; Phenotype; Platelet Activation; Platelet Aggregation Inhibitors; Thrombopoiesis
PubMed: 34615371
DOI: 10.1161/ATVBAHA.121.316373 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Dec 2002The role of cytokines and transcription factors on the regulation of megakaryocy topoiesis and platelet production are reviewed in this article. Megakaryocytopoiesis... (Review)
Review
The role of cytokines and transcription factors on the regulation of megakaryocy topoiesis and platelet production are reviewed in this article. Megakaryocytopoiesis involves the proliferation and differentiation of megakaryocytic pro genitor cells into immature megakaryocytes, and the differentiation of immature megakaryocytes to mature megakaryocytes which produce platelets. The former is regulated mainly by thrombopoietin (TPO) and to a lesser degree by other cytokines such as interleukin-1 (IL-1), IL-3 and platelet-derived growth factor (PDGF), the later by TPO and probably IL-6 and IL-11. A number of transcription factors have been implicated in the control of megakaryocyte differentiation. GATA-1, FOG-1 and Fli-1 are essential regulators in early- and mid-stages of megakaryocytopoiesis. NF-E2 regulates late-stage of megakaryocytopoiesis and platelet production. However, the platelet release mechanism is poorly understood. Nitric oxide (NO) may act in the stage of platelet release through induction of apoptosis in megakaryocytes.
Topics: Animals; Cytokines; DNA-Binding Proteins; Erythroid-Specific DNA-Binding Factors; GATA1 Transcription Factor; Hematopoiesis; Humans; Interleukins; Megakaryocytes; NF-E2 Transcription Factor; NF-E2 Transcription Factor, p45 Subunit; Platelet-Derived Growth Factor; Thrombopoiesis; Thrombopoietin; Transcription Factors
PubMed: 12513728
DOI: No ID Found -
Oncogene Jun 2006Previous studies in cell lines have shown Lyn kinase to be a negative regulator of thrombopoietin (TPO)-induced proliferation. To further investigate the role of Lyn...
Previous studies in cell lines have shown Lyn kinase to be a negative regulator of thrombopoietin (TPO)-induced proliferation. To further investigate the role of Lyn during megakaryocytopoiesis, Lyn-deficient mice (lyn(-/-)) were analyzed. We observed that lyn(-/-) mice have more bone marrow-derived GPIIB (CD41) and Mpl(+) cells when compared to their wild-type littermates. In addition, colony-forming unit-megakaryocytes (CFU-MK) are increased and TPO-induced expansion of primary marrow cells yielded a greater number of mature megakaryocytes (MKs) with increased nuclear ploidy. Histopathology of bone marrow and spleens from lyn(-/-) mice showed an increase in the number of MKs. Mechanistic studies revealed that TPO stimulation of MKs from lyn(-/-) mice did not affect phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT) 3, STAT5, or MAP kinase kinase (MEK). Lyn-deficient MKs supported greater TPO-mediated phosphorylation and kinase activity of both Erk1/2 (mitogen-activated protein kinase, MAPK) and Akt. In contrast, there was a reduction of tyrosine phosphorylation of the inositol phosphatase, SHIP. This is the first direct evidence using primary MKs from Lyn-deficient mice that confirms our prior data from cell lines that Lyn kinase is a negative regulator of TPO signaling.
Topics: Animals; Cell Differentiation; Megakaryocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Thrombocytosis; Thrombopoiesis; Thrombopoietin; src-Family Kinases
PubMed: 16418722
DOI: 10.1038/sj.onc.1209351