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Verhandelingen - Koninklijke Academie... 2004Although platelets were already discovered light-microscopically in the 19th century, it became only clear in 1906 that they originate from megakaryocytes. The discovery... (Review)
Review
Although platelets were already discovered light-microscopically in the 19th century, it became only clear in 1906 that they originate from megakaryocytes. The discovery of thrombopoietin in 1994 facilitated research on the origin of platelets, because this growth factor enabled expansion of megakaryocytes in culture. Thus, cell biological and molecular studies could be undertaken. Knowledge accumulated further by studying mouse models and by unravelling the defect in patients with hereditary thrombocytopenia. How a megakaryocyte originates from a hematopoietic stem cell and how this cell undergoes further maturation and differentiation is a complex process, controlled at different stages by several transcription factor. These transcription factors influence the expression of their own target genes, leading to megakaryocyte maturation and platelet release. One of the transcription factors that is most studied in this regard is GATA1, that forms a transcriptional complex with its cofactor FOG1. Families with hereditary thrombocytopenia have been described due to mutations in the GATA1 gene, and target genes were studied. This broadens our insight in normal megakaryocyte differentiation. The final release of platelets from the megakaryocyte is strongly dependent on the formation of so-called proplatelets. The formation of pseudopodia requires the presence of microtubuli. Beta 1-tubulin is a major part of these microtubuli and plays an important role not only in the genesis of platelets but also in the final discoid form of the platelet. Despite a renewed interest and expanding knowledge in this area, there are more questions than answers at this day.
Topics: Blood Platelets; Cell Differentiation; Humans; Megakaryocytes; Molecular Biology; Research; Thrombopoiesis; Thrombopoietin; Transcription Factors
PubMed: 15074080
DOI: No ID Found -
Current Opinion in Hematology Sep 2011It has become increasingly clear that there are substantial biological differences between fetal/neonatal and adult megakaryopoiesis. Over the last 18 months, studies... (Review)
Review
PURPOSE OF REVIEW
It has become increasingly clear that there are substantial biological differences between fetal/neonatal and adult megakaryopoiesis. Over the last 18 months, studies challenged the paradigm that neonatal megakaryocytes are immature and revealed a developmentally unique uncoupling of proliferation, polyploidization, and cytoplasmic maturation. Several studies also described substantial molecular differences between fetal/neonatal and adult megakaryocytes involving transcription factors, signaling pathways, cytokine receptors, and microRNAs.
RECENT FINDINGS
This review will summarize our current knowledge on the developmental differences between fetal/neonatal and adult megakaryocytes, and recent advances in the underlying molecular mechanisms, including differences in transcription factors, in the response to thrombopoietin (Tpo), and newly described developmentally regulated signaling pathways. We will also discuss the implications of these findings on the way megakaryocytes interact with the environment, the response of neonates to thrombocytopenia, and the pathogenesis of Down syndrome-transient myeloproliferative disorder (TMD) and Down syndrome-acute megakaryoblastic leukemia (DS-AMKL).
SUMMARY
A better characterization of the molecular differences between fetal/neonatal and adult megakaryocytes is critical to elucidating the pathogenesis of a group of disorders that selectively affect fetal/neonatal megakaryocyte progenitors, including the thrombocytopenia-absent radius (TAR) syndrome, Down syndrome-TMD or Down syndrome-AMKL, and the delayed platelet engraftment following cord blood transplantation.
Topics: Adult; Animals; Cell Differentiation; Cellular Microenvironment; Fetus; Gene Expression Regulation, Developmental; Humans; Infant, Newborn; Megakaryocytes; Thrombocytopenia; Thrombopoiesis; Thrombopoietin
PubMed: 21738028
DOI: 10.1097/MOH.0b013e3283497ed5 -
Hematology. American Society of... 2007Thrombocytopenia is a primary manifestation of immune thrombocytopenic purpura (ITP) and may occur as a result of hepatitis C, malignancy, and treatment with... (Review)
Review
Thrombocytopenia is a primary manifestation of immune thrombocytopenic purpura (ITP) and may occur as a result of hepatitis C, malignancy, and treatment with chemotherapy. There is a need for additional means to treat thrombocytopenia in these settings. Recombinant thrombopoietin-like agents became available after the cloning of thrombopoietin in 1994. In clinical trials, these agents showed some efficacy in chemotherapy-induced thrombocytopenia, but their use was ultimately discontinued due to the development of neutralizing antibodies that cross-reacted with endogenous thrombopoietin and caused thrombocytopenia in healthy blood donors and other recipients. Subsequently, "second-generation" thrombopoietic agents without homology to thrombopoietin were developed. In the past 5 years, these second-generation thrombopoeitic growth factors have undergone substantial clinical development and have demonstrated safety, tolerability and efficacy in subjects with ITP and hepatitis C-related thrombocytopenia. These completed studies, many of which are available only in abstract form, and other ongoing studies suggest that thrombopoietic agents will enhance the hematologist's ability to manage these and other causes of thrombocytopenia.
Topics: Hepatitis C; Humans; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thrombocytopenia; Thrombopoiesis
PubMed: 18024617
DOI: 10.1182/asheducation-2007.1.106 -
Thrombosis Research Mar 2019
Topics: Humans; Pituitary Adenylate Cyclase-Activating Polypeptide; Thrombopoiesis
PubMed: 30711811
DOI: 10.1016/j.thromres.2019.01.013 -
Journal of Thrombosis and Haemostasis :... Jun 2015The production of laboratory-generated human platelets is necessary to meet present and future transfusion needs. This manuscript will identify and define the major... (Review)
Review
The production of laboratory-generated human platelets is necessary to meet present and future transfusion needs. This manuscript will identify and define the major roadblocks that must be overcome to make human platelet production possible for clinical use, and propose solutions necessary to accelerate development of laboratory-generated human platelets to market.
Topics: Bioreactors; Blood Platelets; Cell Culture Techniques; Cells, Cultured; Cellular Reprogramming; Gene Expression Regulation, Developmental; Humans; Induced Pluripotent Stem Cells; Megakaryocytes; Phenotype; Platelet Transfusion; Stem Cell Niche; Thrombopoiesis
PubMed: 26149051
DOI: 10.1111/jth.12942 -
Thrombosis Research Aug 2017ATP-binding cassette (ABC) is a family of transporters that facilitates the translocation of substrates across cell membrane using its ATPase subunit. These transporters... (Review)
Review
ATP-binding cassette (ABC) is a family of transporters that facilitates the translocation of substrates across cell membrane using its ATPase subunit. These transporters have key roles in multidrug resistance, lipid homeostasis, antigen processing, immunity, cell proliferation and hematopoiesis. Some ABC transporters are selectively expressed on megakaryocyte progenitor, megakaryocyte and its cellular fragment platelet. However, the role of ABC transporters in hemostasis and thrombosis were not well explored until recently. Studies of both human genetic diseases and genetically-manipulated animal models have greatly improved our understanding of ABC transporters in regulating hematopoiesis particularly megakaryopoiesis and/or platelet activity. Human genome wide association studies (GWAS) have also unraveled the association between ABC transporters and thrombopoiesis in general population. Therefore, this review aims to summarize the recent advances in our understanding of how ABC transporters regulate megakaryopoiesis and platelet activity, the underlining mechanisms and their association with atherosclerosis and atherothrombosis. Last, the emerging therapeutic targets to slow down atherosclerosis development and prevent atherothrombosis via ABC transporters or downstream pathways will also be discussed.
Topics: ATP-Binding Cassette Transporters; Blood Platelets; Coronary Artery Disease; Humans; Platelet Activation; Thrombopoiesis
PubMed: 28641133
DOI: 10.1016/j.thromres.2017.06.020 -
Haematologica May 2023Thrombocytopenia is a thrombopoietin (TPO)-related disorder with very limited treatment options, and can be lifethreatening. There are major problems with typical...
Thrombocytopenia is a thrombopoietin (TPO)-related disorder with very limited treatment options, and can be lifethreatening. There are major problems with typical thrombopoietic agents targeting TPO signaling, so it is urgent to discover a novel TPO-independent mechanism involving thrombopoiesis and potential druggable targets. We developed a drug screening model by the multi-grained cascade forest (gcForest) algorithm and found that 3,8-di-O-methylellagic acid 2- O-glucoside (DMAG) (10, 20 and 40 μM) promoted megakaryocyte differentiation in vitro. Subsequent investigations revealed that DMAG (40 mM) activated ERK1/2, HIF-1b and NF-E2. Inhibition of ERK1/2 blocked megakaryocyte differentiation and attenuated the upregulation of HIF-1b and NF-E2 induced by DMAG. Megakaryocyte differentiation induced by DMAG was inhibited via knockdown of NF-E2. In vivo studies showed that DMAG (5 mg/kg) accelerated platelet recovery and megakaryocyte differentiation in mice with thrombocytopenia. The platelet count of the DMAG-treated group recovered to almost 72% and 96% of the count in the control group at day 10 and 14, respectively. The platelet counts in the DMAG-treated group were almost 1.5- and 1.3-fold higher compared with those of the irradiated group at day 10 and 14, respectively. Moreover, DMAG (10, 25 and 50 mM) stimulated thrombopoiesis in zebrafish. DMAG (5 mg/kg) could also increase platelet levels in c-MPL knockout (c-MPL-/-) mice. In summary, we established a drug screening model through gcForest and demonstrated that DMAG promotes megakaryocyte differentiation via the ERK/HIF1/NF-E2 pathway which, importantly, is independent of the classical TPO/c-MPL pathway. The present study may provide new insights into drug discovery for thrombopoiesis and TPO-independent regulation of thrombopoiesis, as well as a promising avenue for thrombocytopenia treatment.
Topics: Animals; Mice; Anemia; Blood Platelets; Megakaryocytes; Thrombocytopenia; Thrombopoiesis; Thrombopoietin; Zebrafish; Glucosides
PubMed: 36546424
DOI: 10.3324/haematol.2022.282209 -
Advances in Experimental Medicine and... 2014The molecular pathways that regulate megakaryocyte production have historically been identified through multiple candidate gene approaches. Several transcription factors... (Review)
Review
The molecular pathways that regulate megakaryocyte production have historically been identified through multiple candidate gene approaches. Several transcription factors critical for generating megakaryocytes were identified by promoter analysis of megakaryocyte-specific genes, and their biological roles then verified by gene knockout studies; for example, GATA-1, NF-E2, and RUNX1 were identified in this way. In contrast, other transcription factors important for megakaryopoiesis were discovered through a systems approach; for example, c-Myb was found to be critical for the erythroid versus megakaryocyte lineage decision by genome-wide loss-of-function studies. The regulation of the levels of these transcription factors is, for the most part, cell intrinsic, although that assumption has recently been challenged. Epigenetics also impacts megakaryocyte gene expression, mediated by histone acetylation and methylation. Several cytokines have been identified to regulate megakaryocyte survival, proliferation, and differentiation, most prominent of which is thrombopoietin. Upon binding to its receptor, the product of the c-Mpl proto-oncogene, thrombopoietin induces a conformational change that activates a number of secondary messengers that promote cell survival, proliferation, and differentiation, and down-modulate receptor signaling. Among the best studied are the signal transducers and activators of transcription (STAT) proteins; phosphoinositol-3-kinase; mitogen-activated protein kinases; the phosphatases PTEN, SHP1, SHP2, and SHIP1; and the suppressors of cytokine signaling (SOCS) proteins. Additional signals activated by these secondary mediators include mammalian target of rapamycin; β(beta)-catenin; the G proteins Rac1, Rho, and CDC42; several transcription factors, including hypoxia-inducible factor 1α(alpha), the homeobox-containing proteins HOXB4 and HOXA9, and a number of signaling mediators that are reduced, including glycogen synthase kinase 3α(alpha) and the FOXO3 family of forkhead proteins. More recently, systematic interrogation of several aspects of megakaryocyte formation have been conducted, employing genomics, proteomics, and chromatin immunoprecipitation (ChIP) analyses, among others, and have yielded many previously unappreciated signaling mechanisms that regulate megakaryocyte lineage determination, proliferation, and differentiation. This chapter focuses on these pathways in normal and neoplastic megakaryopoiesis, and suggests areas that are ripe for further study.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Lineage; Cytokines; Gene Expression Regulation, Developmental; Genetic Association Studies; Humans; Megakaryocytes; Proto-Oncogene Mas; Systems Biology; Thrombopoiesis
PubMed: 25480637
DOI: 10.1007/978-1-4939-2095-2_4 -
Hematology (Amsterdam, Netherlands) Mar 2011The hematopoietic microenvironment, and in particular the hematopoietic stromal cell element, are intimately involved in megakaryocyte development. The process of... (Review)
Review
The hematopoietic microenvironment, and in particular the hematopoietic stromal cell element, are intimately involved in megakaryocyte development. The process of megakaryocytopoiesis occurs within a complex bone marrow microenvironment where adhesive interactions, chemokines, as well as cytokines play a pivotal role. Here we review the effect of stromal cells and cytokines on megakaryocytopoiesis with the aim of exploring new therapeutic strategies for platelet recovery after hematopoietic stem cell transplantation (HSCT).
Topics: Bone Marrow Cells; Cell Adhesion Molecules; Cytokines; Fetal Blood; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Humans; Platelet Transfusion; Stromal Cells; Thrombopoiesis
PubMed: 21418735
DOI: 10.1179/102453311X12940641877920 -
Frontiers in Immunology 2022Platelets, generated from precursor megakaryocytes (MKs), are central mediators of hemostasis and thrombosis. The process of thrombopoiesis is extremely complex,... (Review)
Review
Platelets, generated from precursor megakaryocytes (MKs), are central mediators of hemostasis and thrombosis. The process of thrombopoiesis is extremely complex, regulated by multiple factors, and related to many cellular events including apoptosis. However, the role of apoptosis in thrombopoiesis has been controversial for many years. Some researchers believe that apoptosis is an ally of thrombopoiesis and platelets production is apoptosis-dependent, while others have suggested that apoptosis is dispensable for thrombopoiesis, and is even inhibited during this process. In this review, we will focus on this conflict, discuss the relationship between megakaryocytopoiesis, thrombopoiesis and apoptosis. In addition, we also consider why such a vast number of studies draw opposite conclusions of the role of apoptosis in thrombopoiesis, and try to figure out the truth behind the mystery. This review provides more comprehensive insights into the relationship between megakaryocytopoiesis, thrombopoiesis, and apoptosis and finds some clues for the possible pathological mechanisms of platelet disorders caused by abnormal apoptosis.
Topics: Megakaryocytes; Thrombopoiesis; Blood Platelets; Hemostasis; Apoptosis; Fenbendazole
PubMed: 36685543
DOI: 10.3389/fimmu.2022.1025945