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International Journal of Molecular... Jun 2019In women, oral menopausal hormonal therapy (MHT) is associated with adverse effects including an increased incidence of thromboembolic events, classically attributed to... (Review)
Review
In women, oral menopausal hormonal therapy (MHT) is associated with adverse effects including an increased incidence of thromboembolic events, classically attributed to an increase in several liver-derived coagulation factors due to hepatic first pass. While platelets are central players in thrombus constitution, their implication in women treated with estrogens remains incompletely characterized. Platelets and their medullar progenitors, megakaryocytes, express estrogen receptors (ER) that may explain, at least in part, a sensitivity to hormonal changes. The purpose of this review is to summarize our current knowledge of estrogen actions on platelets and megakaryocytes in mice following in vivo administration and in women using MHT.
Topics: Animals; Blood Platelets; Estrogens; Female; Humans; Megakaryocytes; Platelet Activation; Sex Factors; Thrombopoiesis
PubMed: 31242705
DOI: 10.3390/ijms20123111 -
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 :... Nov 2023Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune...
BACKGROUND
Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune thrombocytopenia. However, their efficacy and mechanisms of action in immune thrombocytopenia are not fully understood.
OBJECTIVES
To investigate the mechanism of glucocorticoid actions on platelet production.
METHODS
The actions of glucocorticoids on platelet production were studied combining in vivo, ex vivo and in vitro approaches.
RESULTS
Dexamethasone reduced bleeding in mice and rapidly increased circulating young platelet counts. In vitro glucocorticoid treatment stimulated proplatelet formation by megakaryocytes and platelet-like particle release. This effect was blocked by glucocorticoid receptor antagonist RU486, indicating a glucocorticoid receptor-dependent mechanism. Genome-wide analysis revealed that dexamethasone regulates the expression of >1000 genes related to numerous cellular functions, including predominant cytoplasm and cytoskeleton reorganization. Dexamethasone and other glucocorticoids induced the expression of Gda (the gene encoding guanine deaminase), which has been reported to have a role in dendrite development. Inhibition of guanine deaminase enzymatic activity blocked dexamethasone stimulation of proplatelet formation, implicating a critical role for this enzyme in glucocorticoid-mediated platelet production.
CONCLUSION
Our findings identify glucocorticoids as new regulators of thrombopoiesis.
Topics: Mice; Animals; Megakaryocytes; Thrombopoiesis; Glucocorticoids; Purpura, Thrombocytopenic, Idiopathic; Receptors, Glucocorticoid; Guanine Deaminase; Transcriptome; Blood Platelets; Thrombocytopenia; Dexamethasone
PubMed: 37336437
DOI: 10.1016/j.jtha.2023.06.012 -
Blood Mar 2016Thrombocytopenia is defined as a status in which platelet numbers are reduced. Imbalance between the homeostatic regulation of platelet generation and destruction is 1... (Review)
Review
Thrombocytopenia is defined as a status in which platelet numbers are reduced. Imbalance between the homeostatic regulation of platelet generation and destruction is 1 potential cause of thrombocytopenia. In adults, platelet generation is a 2-stage process entailing the differentiation of hematopoietic stem cells into mature megakaryocytes (MKs; known as megakaryopoiesis) and release of platelets from MKs (known as thrombopoiesis or platelet biogenesis). Until recently, information about the genetic defects responsible for congenital thrombocytopenia was only available for a few forms of the disease. However, investigations over the past 15 years have identified mutations in genes encoding >20 different proteins that are responsible for these disorders, which has advanced our understanding of megakaryopoiesis and thrombopoiesis. The underlying pathogenic mechanisms can be categorized as (1) defects in MK lineage commitment and differentiation, (2) defects in MK maturation, and (3) defect in platelet release. Using these developmental stage categories, we here update recently described mechanisms underlying megakaryopoiesis and thrombopoiesis and discuss the association between platelet generation systems and thrombocytopenia.
Topics: Adult; Animals; Genetic Diseases, Inborn; Hematopoietic Stem Cells; Humans; Megakaryocytes; Mutation; Thrombocytopenia; Thrombopoiesis
PubMed: 26787737
DOI: 10.1182/blood-2015-07-607903 -
Blood Jun 2016Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide... (Review)
Review
Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).(1) The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein-protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.
Topics: Blood Platelet Disorders; Blood Platelets; DNA; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Molecular Diagnostic Techniques; Rare Diseases; Thrombopoiesis
PubMed: 27095789
DOI: 10.1182/blood-2016-03-378588 -
Blood Jun 2022Fetal and neonatal megakaryocyte progenitors are hyperproliferative compared with adult progenitors and generate a large number of small, low-ploidy megakaryocytes....
Fetal and neonatal megakaryocyte progenitors are hyperproliferative compared with adult progenitors and generate a large number of small, low-ploidy megakaryocytes. Historically, these developmental differences have been interpreted as "immaturity." However, more recent studies have demonstrated that the small, low-ploidy fetal and neonatal megakaryocytes have all the characteristics of adult polyploid megakaryocytes, including the presence of granules, a well-developed demarcation membrane system, and proplatelet formation. Thus, rather than immaturity, the features of fetal and neonatal megakaryopoiesis reflect a developmentally unique uncoupling of proliferation, polyploidization, and cytoplasmic maturation, which allows fetuses and neonates to populate their rapidly expanding bone marrow and blood volume. At the molecular level, the features of fetal and neonatal megakaryopoiesis are the result of a complex interplay of developmentally regulated pathways and environmental signals from the different hematopoietic niches. Over the past few years, studies have challenged traditional paradigms about the origin of the megakaryocyte lineage in both fetal and adult life, and the application of single-cell RNA sequencing has led to a better characterization of embryonic, fetal, and adult megakaryocytes. In particular, a growing body of data suggests that at all stages of development, the various functions of megakaryocytes are not fulfilled by the megakaryocyte population as a whole, but rather by distinct megakaryocyte subpopulations with dedicated roles. Finally, recent studies have provided novel insights into the mechanisms underlying developmental disorders of megakaryopoiesis, which either uniquely affect fetuses and neonates or have different clinical presentations in neonatal compared with adult life.
Topics: Adult; Bone Marrow; Fetus; Humans; Infant, Newborn; Megakaryocyte Progenitor Cells; Megakaryocytes; Thrombopoiesis
PubMed: 35108353
DOI: 10.1182/blood.2020009301 -
Haematologica Mar 2021Sialic acid is a common terminal residue of glycans on proteins and acidic sphingolipids such as gangliosides and has important biological functions. The sialylation...
Sialic acid is a common terminal residue of glycans on proteins and acidic sphingolipids such as gangliosides and has important biological functions. The sialylation process is controlled by more than 20 different sialyltransferases, many of which exhibit overlapping functions. Thus, it is difficult to determine the overall biological function of sialylation by targeted deletion of individual sialyltransferases. To address this issue, we established a mouse line with the Slc35a1 gene flanked by loxP sites. Slc35a1 encodes the cytidine-5’-monophosphate (CMP)-sialic acid transporter that transports CMP-sialic acid from the cytoplasm into the Golgi apparatus for sialylation. Here we report our study regarding the role of sialylation on megakaryocytes and platelets using a mouse line with significantly reduced sialylation in megakaryocytes and platelets (Plt Slc35a1– /–). The major phenotype of Plt Slc35a1–/– mice was thrombocytopenia. The number of bone marrow megakaryocytes in Plt Slc35a1–/– mice was reduced, and megakaryocyte maturation was also impaired. In addition, an increased number of desialylated platelets was cleared by Küpffer cells in the liver of Plt Slc35a1–/– mice. This study provides new insights into the role of sialylation in platelet homeostasis and the mechanisms of thrombocytopenia in diseases associated with platelet desialylation, such as immune thrombocytopenia and a rare congenital disorder of glycosylation (CDG), SLC35A1-CDG, which is caused by SLC35A1 mutations.
Topics: Blood Platelets; Humans; Liver; N-Acetylneuraminic Acid; Nucleotide Transport Proteins; Thrombocytopenia; Thrombopoiesis
PubMed: 32303557
DOI: 10.3324/haematol.2019.225987 -
British Journal of Haematology Apr 2014In the two decades since its cloning, thrombopoietin (TPO) has emerged not only as a critical haematopoietic cytokine, but also serves as a great example of... (Review)
Review
In the two decades since its cloning, thrombopoietin (TPO) has emerged not only as a critical haematopoietic cytokine, but also serves as a great example of bench-to-bedside research. Thrombopoietin, produced by the liver, is the primary regulator of megakaryocyte progenitor expansion and differentiation. Additionally, as TPO is vital for the maintenance of haematopoietic stem cells, it can truly be described as a pan-haematopoietic cytokine. Since recombinant TPO became available, the molecular mechanisms of TPO function have been the subject of extensive research. Via its receptor, c-Mpl (also termed MPL), TPO activates a wide array of downstream signalling pathways, promoting cellular survival and proliferation. Due to its central, non-redundant role in haematopoiesis, alterations of both the hormone and its receptor contribute to human disease; congenital and acquired states of thrombocytosis and thrombocytopenia and aplastic anaemia as a result from dysregulated TPO expression or functional alterations of c-Mpl. With TPO mimetics now in clinical use, the story of this haematopoietic cytokine represents a great success for biomedical research.
Topics: Animals; Blood Platelets; Cloning, Molecular; Gene Expression Regulation; Hematopoietic Stem Cells; Humans; Receptors, Thrombopoietin; Signal Transduction; Thrombopoiesis; Thrombopoietin
PubMed: 24499199
DOI: 10.1111/bjh.12772 -
International Journal of Biological... 2023Abnormal megakaryocyte maturation and platelet production lead to platelet-related diseases and impact the dynamic balance between hemostasis and bleeding. Cellular...
Abnormal megakaryocyte maturation and platelet production lead to platelet-related diseases and impact the dynamic balance between hemostasis and bleeding. Cellular repressor of E1A-stimulated gene 1 (CREG1) is a glycoprotein that promotes tissue differentiation. However, its role in megakaryocytes remains unclear. In this study, we found that CREG1 protein is expressed in platelets and megakaryocytes and was decreased in the platelets of patients with thrombocytopenia. A cytosine arabinoside-induced thrombocytopenia mouse model was established, and the mRNA and protein expression levels of CREG1 were found to be reduced in megakaryocytes. We established megakaryocyte/platelet conditional knockout () and transgenic mice (tg-). Compared to mice, mice exhibited thrombocytopenia, which was mainly caused by inefficient bone marrow (BM) thrombocytopoiesis, but not by apoptosis of circulating platelets. Cultured -megakaryocytes exhibited impairment of the actin cytoskeleton, with less filamentous actin, significantly fewer proplatelets, and lower ploidy. CREG1 directly interacts with MEK1/2 and promotes MEK1/2 phosphorylation. Thus, our study uncovered the role of CREG1 in the regulation of megakaryocyte maturation and thrombopoiesis, and it provides a possible theoretical basis for the prevention and treatment of thrombocytopenia.
Topics: Animals; Mice; Blood Platelets; Bone Marrow; Megakaryocytes; Mice, Transgenic; Thrombocytopenia; Thrombopoiesis; Humans
PubMed: 37496998
DOI: 10.7150/ijbs.78660 -
Journal of Thrombosis and Haemostasis :... Aug 2005Megakaryocytes (MKs) expand and differentiate over several days in response to thrombopoietin (Tpo) before releasing innumerable blood platelets. The final steps in... (Review)
Review
Megakaryocytes (MKs) expand and differentiate over several days in response to thrombopoietin (Tpo) before releasing innumerable blood platelets. The final steps in platelet assembly and release represent a unique cellular transformation that is orchestrated by a range of transcription factors, signaling molecules, and cytoskeletal elements. Here we review recent advances in the physiology and molecular basis of MK differentiation. Genome-wide approaches, including transcriptional profiling and proteomics, have been used to identify novel platelet products and differentiation markers. The extracellular factors, stromal-derived factor (SDF)-1 chemokine and fibroblast growth factor (FGF)-4 direct MK interactions with the bone marrow stroma and regulate cytokine-independent cell maturation. An abundance of bone marrow MKs induce pathologic states, including excessive bone formation and myelofibrosis, and the basis for these effects is now better appreciated. We review the status of transcription factors that control MK differentiation, with special emphasis on nuclear factor-erythroid 2 (NF-E2) and its two putative target genes, beta1-tubulin and 3-beta-hydroxysteroid reductase. MKs express steroid receptors and some estrogen ligands, which may constitute an autocrine loop in formation of proplatelets, the cytoplasmic protrusions within which nascent blood platelets are assembled. Finally, we summarize our own studies on cellular and molecular facets of proplatelet formation and place the findings within the context of outstanding questions about mechanisms of thrombopoiesis.
Topics: Animals; Blood Platelets; Cell Differentiation; Chemokine CXCL12; Chemokines, CXC; Cytoplasm; Genome; Humans; Megakaryocytes; Microtubules; Protein Binding; Proteomics; Signal Transduction; Thrombopoiesis; Transcription Factors; Transcription, Genetic
PubMed: 16102038
DOI: 10.1111/j.1538-7836.2005.01426.x