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Der Radiologe Dec 2021Bone marrow consists of connective tissue and stem cells, which generate blood cells. This includes erythropoiesis, leukopoiesis and thrombopoiesis. Thus, hematologic... (Review)
Review
BACKGROUND
Bone marrow consists of connective tissue and stem cells, which generate blood cells. This includes erythropoiesis, leukopoiesis and thrombopoiesis. Thus, hematologic disorders first affect the bone marrow and secondarily the blood.
METHODS
Bone marrow changes can be sensitively detected using magnetic resonance imaging (MRI) and often represent the initial manifestation of the underlying disease. With longer duration of disease, changes can also be found on X‑ray or computed tomography (CT).
RESULTS
The findings on MRI and X‑ray/CT are often nonspecific and can only be interpreted in the context of clinical information.
CONCLUSION
In the following article, we provide a brief overview of the clinical manifestations and imaging changes to be expected in leukemia, anemia, and chronic myeloproliferative disorders.
Topics: Bone Marrow; Hematologic Diseases; Humans; Magnetic Resonance Imaging; Musculoskeletal System; Tomography, X-Ray Computed
PubMed: 34820696
DOI: 10.1007/s00117-021-00934-z -
Nature Communications Jul 2023Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms...
Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms remain unclear. Outside the body, however, our ability to generate large number of functional platelets is poor. Here we show that perfusion of megakaryocytes ex vivo through the mouse lung vasculature generates substantial platelet numbers, up to 3000 per megakaryocyte. Despite their large size, megakaryocytes are able repeatedly to passage through the lung vasculature, leading to enucleation and subsequent platelet generation intravascularly. Using ex vivo lung and an in vitro microfluidic chamber we determine how oxygenation, ventilation, healthy pulmonary endothelium and the microvascular structure support thrombopoiesis. We also show a critical role for the actin regulator Tropomyosin 4 in the final steps of platelet formation in lung vasculature. This work reveals the mechanisms of thrombopoiesis in lung vasculature and informs approaches to large-scale generation of platelets.
Topics: Mice; Animals; Blood Platelets; Microfluidics; Megakaryocytes; Thrombopoiesis; Lung
PubMed: 37419900
DOI: 10.1038/s41467-023-39598-9 -
Stem Cell Reviews and Reports Oct 2019For decades, megakaryocytopoiesis is believed to occur following a classical binary hierarchical developmental model. This model is based on an analysis of predefined... (Review)
Review
For decades, megakaryocytopoiesis is believed to occur following a classical binary hierarchical developmental model. This model is based on an analysis of predefined flow-sorted cell populations by using cell surface markers. However, this classical model has been challenged by increasing evidences obtained with new techniques which integrating flow cytometric, transcriptomic and functional data at single-cell level and with lineage tracing technique. These recent advances in megakaryocytopoiesis proposed that commitment of haematopoietic stem cells (HSCs) towards megakaryocytic lineage occurs in much earlier stage than that postulated in the classical model. There may exist multipotent but megakaryocyte (MK)/platelet-biased HSCs within HSC compartment and even HSCs can directly differentiate into MKs in steady state or in response to stress. In this review, we focus on recent findings about differentiation from commitment of HSCs to MK and its regulation, and discuss future directions in this research field.
Topics: Animals; Blood Platelets; Cell Differentiation; Cell Lineage; Hematopoietic Stem Cells; Humans; Megakaryocytes
PubMed: 31230184
DOI: 10.1007/s12015-019-09905-3 -
International Journal of Molecular... Mar 2023Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological... (Review)
Review
Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in and is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.
Topics: Humans; Glycosylation; Thrombocytopenia; Blood Platelets; Megakaryocytes; Thrombopoiesis; Thrombopoietin; Nucleotide Transport Proteins
PubMed: 36982178
DOI: 10.3390/ijms24065109 -
Faculty Reviews 2021Thrombocytopoiesis is a complex process beginning at the level of hematopoietic stem cells, which ultimately generate megakaryocytes, large marrow cells with a... (Review)
Review
Thrombocytopoiesis is a complex process beginning at the level of hematopoietic stem cells, which ultimately generate megakaryocytes, large marrow cells with a distinctive morphology, and then, through a process of terminal maturation, megakaryocytes shed thousands of platelets into the circulation. This process is controlled by intrinsic and extrinsic factors. Emerging data indicate that an important intrinsic control on the late stages of thrombopoiesis is exerted by integrins, a family of transmembrane receptors composed of one α and one β subunit. One β subunit expressed by megakaryocytes is the β1 integrin, the role of which in the regulation of platelet formation is beginning to be clarified. Here, we review recent data indicating that activation of β1 integrin by outside-in and inside-out signaling regulates the interaction of megakaryocytes with the endosteal niche, which triggers their maturation, while its inactivation by galactosylation determines the migration of these cells to the perivascular niche, where they complete their terminal maturation and release platelets in the bloodstream. Furthermore, β1 integrin mediates the activation of transforming growth factor β (TGF-β), a protein produced by megakaryocytes that may act in an autocrine fashion to halt their maturation and affect the composition of their surrounding extracellular matrix. These findings suggest that β1 integrin could be a therapeutic target for inherited and acquired disorders of platelet production.
PubMed: 34557872
DOI: 10.12703/r/10-68 -
Haematologica Aug 2020Over the last 100 years the role of platelets in hemostatic events and their production by megakaryocytes have gradually been defined. Progressively, thrombocytopenia... (Review)
Review
Over the last 100 years the role of platelets in hemostatic events and their production by megakaryocytes have gradually been defined. Progressively, thrombocytopenia was recognized as a cause of bleeding, first through an acquired immune disorder; then, since 1948, when Bernard-Soulier syndrome was first described, inherited thrombocytopenia became a fascinating example of Mendelian disease. The platelet count is often severely decreased and platelet size variable; associated platelet function defects frequently aggravate bleeding. Macrothrombocytopenia with variable proportions of enlarged platelets is common. The number of circulating platelets will depend on platelet production, consumption and lifespan. The bulk of macrothrombocytopenias arise from defects in megakaryopoiesis with causal variants in transcription factor genes giving rise to altered stem cell differentiation and changes in early megakaryocyte development and maturation. Genes encoding surface receptors, cytoskeletal and signaling proteins also feature prominently and Sanger sequencing associated with careful phenotyping has allowed their early classification. It quickly became apparent that many inherited thrombocytopenias are syndromic while others are linked to an increased risk of hematologic malignancies. In the last decade, the application of next-generation sequencing, including whole exome sequencing, and the use of gene platforms for rapid testing have greatly accelerated the discovery of causal genes and extended the list of variants in more common disorders. Genes linked to an increased platelet turnover and apoptosis have also been identified. The current challenges are now to use next-generation sequencing in first-step screening and to define bleeding risk and treatment better.
Topics: Bernard-Soulier Syndrome; Blood Platelets; Humans; Megakaryocytes; Thrombocytopenia; Thrombopoiesis
PubMed: 32527953
DOI: 10.3324/haematol.2019.233197 -
Cytokine Sep 2021Cytokines are key mediators of immune responses to autoantigens, tumor antigens and foreign antigens including pathogens and transplant antigens. The cytokines are... (Review)
Review
Cytokines are key mediators of immune responses to autoantigens, tumor antigens and foreign antigens including pathogens and transplant antigens. The cytokines are produced by a variety of immune and non-immune cells and are dynamically regulated. Remarkably, during toxic and septic shock syndromes, anaphylactic shock and in certain viral infections supra-physiologic levels of cytokine storms are produced culminating in multi-organ failure and death. However, Leishmania infection is a chronic parasitic infection with alternate outcomes- healing or non-healing. Leishmania invades macrophages and inflicts the complex of diseases called Leishmaniases. Depending on the species of Leishmania and the organs affected, the diseases are categorized into Cutaneous Leishmaniasis (CL), Muco-cutaneous Leishmaniasis (MCL) and Visceral Leishmaniasis (VL). After successful chemotherapy of VL, a dermal manifestation- termed post-kalazar dermal leishmaniasis (PKDL)- of the same infection occurs in some patients. The operational frameworks for different cytokines have been laid to discuss how these immune mediators control each of these forms of leishmaniases. One of these frameworks is the regulation of monocytopoiesis including the role of macrophages subsets and thrombopoiesis in leishmaniases. Macrophage metabolism is linked to different cytokines and is thereby associated with the manifestation of the resistance or susceptibility to Leishmania infection and of drug resistance. The chemokine-regulated immune cell movements present the landscape of infection and pathogenesis. T cells subsets- the IFN-γ-secreting Ly6C + T cells and the regulatory T cell subsets- provide the initial skewing of Th cell subset and regulation of effector Th subsets, respectively, eventually deciding the outcome of infection.
Topics: Animals; Cytokines; Humans; Immunity; Leishmania; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Macrophages; Monocytes; T-Lymphocyte Subsets; Thrombopoiesis
PubMed: 33127260
DOI: 10.1016/j.cyto.2020.155320 -
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 -
Frontiers in Immunology 2019Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed... (Review)
Review
Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed various intersection points between thrombosis, hemostasis, and inflammation, which are addressed and discussed in this review in detail. One such example is the intrinsic coagulation cascade that is initiated after platelet activation thereby further propagating and re-enforcing wound healing or thrombus formation but also contributing to the pathophysiology of severe diseases. FXII of the intrinsic pathway connects platelet activation with the coagulation cascade during immune reactions. It can activate the contact system thereby either creating an inflammatory state or accelerating inflammation. Recent insights into platelet biology could show that platelets are equipped with complement receptors. Platelets are important for tissue remodeling after injury has been inflicted to the endothelial barrier and to the subendothelial tissue. Thus, platelets are increasingly recognized as more than just cells relevant for bleeding arrest. Future insights into platelet biology are to be expected. This research will potentially offer novel opportunities for therapeutic intervention in diseases featuring platelet abundance.
Topics: Animals; Blood Platelets; Bone Marrow; Complement System Proteins; Disease Susceptibility; Humans; Immunity; Immunity, Innate; Inflammation; Platelet Activation; Platelet Membrane Glycoproteins; Protein Binding; Signal Transduction; Thrombopoiesis; Thrombosis
PubMed: 31402914
DOI: 10.3389/fimmu.2019.01731 -
Journal of Thrombosis and Haemostasis :... Nov 2023Megakaryocyte differentiation and platelet production disorders are the main causes of thrombocythemia and thrombocytopenia and lead to thrombosis or hemorrhage....
BACKGROUND
Megakaryocyte differentiation and platelet production disorders are the main causes of thrombocythemia and thrombocytopenia and lead to thrombosis or hemorrhage. Branched-chain amino acids (BCAAs) are essential nutrients that regulate important metabolic signals. BCAA administration could also increase platelet activation and promote the risk of thrombosis.
OBJECTIVES
To unveil the role of BCAAs in thrombocytopoiesis.
METHODS
BCAA-fed mice and megakaryocyte/platelet-specific branched-chain α-keto acid dehydrogenase E1α subunit-deficient mice were used to study the role of BCAAs in thrombocytopoiesis.
RESULTS
In this study, we found that BCAA diet could facilitate megakaryocyte differentiation and platelet production. Meanwhile, megakaryocyte/platelet-specific branched-chain α-keto acid dehydrogenase E1α subunit-deficient mice developed thrombocythemia, which was mainly caused by the excessive differentiation of megakaryocytes and proplatelet biogenesis. Moreover, the use of BT2, the agonist of BCAA catabolism, could affect proplatelet formation (PPF) and megakaryocyte polyploidization, as well as ameliorating the thrombocythemia of BCAA-fed mice.
CONCLUSION
We found that deficiency in BCAA catabolism led to the activation of p70S6K/mammalian target of rapamycin (mTOR) signaling, megakaryocyte over differentiation, and the acceleration of PPF. Activating BCAA metabolism with BT2 could inhibit mTOR signaling, reduce PPF, and ameliorate thrombocythemia in BCAA-fed mice. Therefore, this study reveals a novel role of BCAAs in megakaryocyte differentiation and platelet production, suggesting that targeting BCAA-mediated p70S6K/mTOR signaling may be a potential strategy for the treatment of thrombocytopenia or thrombocythemia.
Topics: Mice; Animals; Amino Acids, Branched-Chain; Ribosomal Protein S6 Kinases, 70-kDa; Thrombopoiesis; 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); TOR Serine-Threonine Kinases; Thrombocytosis; Thrombocytopenia; Thrombosis; Mammals
PubMed: 37473846
DOI: 10.1016/j.jtha.2023.06.039