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Platelets Aug 2020A growing body of research has made it increasingly clear that there are substantial biological differences between fetal/neonatal and adult megakaryopoiesis. Over the... (Review)
Review
A growing body of research has made it increasingly clear that there are substantial biological differences between fetal/neonatal and adult megakaryopoiesis. Over the last decade, studies revealed a developmentally unique uncoupling of proliferation, polyploidization, and cytoplasmic maturation in neonatal MKs that results in the production of large numbers of small, low ploidy, but mature MKs during this period of development, and identified substantial molecular differences between fetal/neonatal and adult MKs. This review will summarize our current knowledge on the developmental differences between fetal/neonatal and adult MKs, and recent advances in our understanding of the underlying molecular mechanisms, including newly described developmentally regulated pathways and miRNAs. We will also discuss the implications of these findings on the ways MKs interact with the environment, the response of neonates to thrombocytopenia, the pathogenesis of Down syndrome-transient myeloproliferative disorder (TMD), and the developmental stage specific-manifestations of congenital amegakaryocytic thrombocytopenia.
Topics: Animals; Cell Differentiation; Gene Expression Regulation, Neoplastic; Humans; Mice; Thrombopoiesis
PubMed: 32200697
DOI: 10.1080/09537104.2020.1742879 -
Journal of Thrombosis and Haemostasis :... Nov 2022Developmental ontogeny of neonatal thrombopoiesis retains characteristics that are distinct from adults although molecular mechanisms remain unestablished.
BACKGROUND
Developmental ontogeny of neonatal thrombopoiesis retains characteristics that are distinct from adults although molecular mechanisms remain unestablished.
METHODS
We applied multiparameter quantitative platelet responses with integrated ribosome profiling/transcriptomic studies to better define gene/pathway perturbations regulating the neonatal-to-adult transition. A bioinformatics pipeline was developed to identify stable, neonatal-restricted platelet biomarkers for clinical application.
RESULTS
Cord blood (CB) platelets retained the capacity for linear agonist-receptor coupling linked to phosphatidylserine (PS) exposure and α-granule release, although a restricted block in cross-agonist activation pathways was evident. Functional immaturity of synergistic signaling pathways was due to younger ontogenetic age and singular underdevelopment of the protein secretory gene network, with reciprocal expansion of developmental pathways (E2F, G2M checkpoint, c-Myc) important for megakaryocytopoiesis. Genetic perturbations regulating vesicle transport and fusion (TOM1L1, VAMP3, SNAP23, and DNM1L) and PS exposure and procoagulant activity (CLCN3) were the most significant, providing a molecular explanation for globally attenuated responses. Integrated transcriptomic and ribosomal footprints identified highly abundant (ribosome-protected) DEFA3 (encoding human defensin neutrophil peptide 3) and HBG1 as stable biomarkers of neonatal thrombopoiesis. Studies comparing CB- or adult-derived megakaryocytopoiesis confirmed inducible and abundant DEFA3 antigenic expression in CB megakaryocytes, ~3.5-fold greater than in leukocytes (the most abundant source in humans). An initial feasibility cohort of at-risk pregnancies manifested by maternal/fetal hemorrhage (chimerism) were applied for detection and validation of platelet HBG1 and DEFA3 as neonatal thrombopoiesis markers, most consistent for HBG1, which displayed gestational age-dependent expression.
CONCLUSIONS
These studies establish an ontogenetically divergent stage of neonatal thrombopoiesis, and provide initial feasibility studies to track disordered fetal-to-adult megakaryocytopoiesis in vivo.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Blood Platelets; Phosphatidylserines; Vesicle-Associated Membrane Protein 3; Thrombopoiesis; Megakaryocytes; Peptides; Defensins; Adaptor Proteins, Signal Transducing
PubMed: 35962592
DOI: 10.1111/jth.15847 -
Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation.Nature Cardiovascular Research Sep 2023During megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a...
During megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a lipid-centric multiomics approach to create a quantitative map of the MK lipidome during maturation and proplatelet formation. Data reveal that MK differentiation is driven by an increased fatty acyl import and lipid synthesis, resulting in an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis blocked membrane remodeling and directly reduced MK polyploidization and proplatelet formation resulting in thrombocytopenia. The anionic lipid shift during megakaryopoiesis was paralleled by lipid-dependent relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which seems to be essential for sufficient platelet biogenesis. Overall, this study provides a framework to understand how the MK lipidome is altered during maturation and the impact of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.
PubMed: 38075556
DOI: 10.1038/s44161-023-00325-8 -
Thrombosis Journal Oct 2023Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease characterized by increased platelet destruction and impaired thrombopoiesis. The changes in platelet...
BACKGROUND
Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease characterized by increased platelet destruction and impaired thrombopoiesis. The changes in platelet indices depend on the morphology and volume of platelets. Serum lipids have been found to affect platelet formation and activity in certain diseases, thus inducing the corresponding variation of platelet indices.
METHODS
Mendelian randomization (MR) analysis was performed based on databases. The clinical data from 457 ITP patients were retrospectively collected and analyzed, including platelet indices, serum lipids, hemorrhages and therapeutic responses.
RESULTS
MR analysis showed low high-density-lipoprotein-cholesterol (HDL-C), low apolipoprotein A-1, high triglyceride (TG) and high apolipoprotein B (ApoB) caused high platelet distribution width (PDW); high low-density-lipoprotein-cholesterol (LDL-C) increased mean platelet volume (MPV). In ITP, there were positive correlations between platelet count with TG, PDW with HDL-C and ApoB, and plateletcrit with TG and non-esterified fatty acid, and the correlation had gender differences. Bleeding scores were negatively correlated with cholesterol and LDL-C. LDL-C and homocysteine were risk factors for therapeutic responses.
CONCLUSIONS
Serum lipids, especially cholesterol were tightly correlated with platelet indices, hemorrhage and therapeutic effects in ITP patients. These results provide clinical references for the management of serum lipids, and highlight the necessity to further explore the relationship between lipids and pathogenesis of ITP.
TRIAL REGISTRATION
No: NCT05095896, October 14, 2021, retrospectively registered.
PubMed: 37833799
DOI: 10.1186/s12959-023-00551-x -
Cells Nov 2021Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at... (Review)
Review
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at least involve autoantibody-dependent and/or cytotoxic T cell mediated platelet clearance and impaired megakaryopoiesis. In addition, T cell imbalances involving T regulatory cells (Tregs) also appear to play an important role. Intriguingly, over the past years it has become evident that platelets not only mediate hemostasis, but are able to modulate inflammatory and immunological processes upon activation. Platelets, therefore, might play an immuno-modulatory role in the pathogenesis and pathophysiology of ITP. In this respect, we propose several possible pathways in which platelets themselves may participate in the immune response in ITP. First, we will elaborate on how platelets might directly promote inflammation or stimulate immune responses in ITP. Second, we will discuss two ways in which platelet microparticles (PMPs) might contribute to the disrupted immune balance and impaired thrombopoiesis by megakaryocytes in ITP. Importantly, from these insights, new starting points for further research and for the design of potential future therapies for ITP can be envisioned.
Topics: Blood Platelets; Bone Marrow; Cell-Derived Microparticles; Humans; Immunity; Models, Biological; Purpura, Thrombocytopenic, Idiopathic
PubMed: 34831457
DOI: 10.3390/cells10113235 -
Journal of Veterinary Internal Medicine Jan 2022Carcinoma-associated thrombocytosis involves tumor production of mediators such as interleukin-6 (IL-6) and thrombopoietin (TPO) that increase thrombopoiesis and may...
BACKGROUND
Carcinoma-associated thrombocytosis involves tumor production of mediators such as interleukin-6 (IL-6) and thrombopoietin (TPO) that increase thrombopoiesis and may play a role in tumor evasion and metastasis. Carcinoma-associated thrombocytosis is described in people, but has not been described in dogs.
HYPOTHESIS/OBJECTIVES
Evaluate the concentrations of IL-6 and TPO in dogs diagnosed with carcinoma with or without thrombocytosis. We hypothesized that IL-6 and TPO concentrations would be higher in dogs with carcinoma compared to healthy dogs, and that IL-6 and TPO concentrations would be higher in dogs with carcinoma and thrombocytosis when compared to dogs with carcinoma and normal platelet counts.
ANIMALS
One-hundred sixteen dogs: 63 with carcinoma and 53 healthy control dogs.
METHODS
Complete blood count was performed in all dogs, and they were stratified for sub-group analysis based on the presence or absence of thrombocytosis (platelet count > 500 103/µL). Serum TPO and IL-6 concentrations were measured by ELISA. Results of selected numeric variables were compared using Wilcoxon rank sum tests for pairwise comparisons. A value of P < .05 was considered significant.
RESULTS
Twelve of the dogs with carcinoma (12/63, 19.0%) and none of the healthy control dogs (0%) had thrombocytosis. Thrombopoietin concentrations (median [range]) were significantly higher in dogs with carcinoma when compared to controls (87.42 pg/mL [0 to >600] vs 15.99 pg/mL [0 to >600], P < .001). Interleukin-6 concentrations (median [range]) were not different between dogs with carcinoma and healthy control dogs (9.70 pg/mL [0-181.53] vs 3.03 pg/mL [0-280.77], P = .15). In dogs with carcinoma, the TPO and IL-6 concentrations were not different between dogs with thrombocytosis and dogs with normal platelet count.
CONCLUSIONS AND CLINICAL IMPORTANCE
Thrombopoietin concentrations were significantly higher in dogs with carcinoma, regardless of platelet count. Thrombopoietin is likely to be 1 of multiple factors that can impact platelet number, production, and consumption in dogs with carcinoma.
Topics: Animals; Carcinoma; Case-Control Studies; Dog Diseases; Dogs; Interleukin-6; Platelet Count; Thrombocytosis; Thrombopoietin
PubMed: 34881459
DOI: 10.1111/jvim.16317 -
Advances in Experimental Medicine and... 2020Platelet and blood transfusions have vital importance to the lives of many patients. Platelet transfusions are a life-saving intervention by reducing risk of bleeding in... (Review)
Review
Platelet and blood transfusions have vital importance to the lives of many patients. Platelet transfusions are a life-saving intervention by reducing risk of bleeding in thrombocytopenic patients. Due to the short shelf life of platelets and their limited availability, researchers have developed various platelet transfusion production technologies. Understanding the cellular and biophysical mechanisms of platelet release is particularly important for development of platelet transfusion products (PTPs) and to translate them to clinical applications in patients requiring platelet infusion. Similarly, due to donor dependence and increased clinical need of blood transfusions, studies on the erythroid transfusion products (ETPs) have recently gained momentum. This led to development of ETP technologies involving differentiation of stem cells to fully functional erythrocytes in vitro. During megakaryopoiesis or erythropoiesis, various stimulatory factors, growth factors, transcription factors, and biophysical conditions have been shown to play a crucial role in the formation final blood products. Thus, understanding of the in vivo mechanisms of platelet release and erythrocyte maturation is particularly important for mimicking these conditions in vitro. This review focuses on latest and up-to-date information about the innovations in PTP and ETP technologies. We also discuss some of the recent fundamental findings that have changed our understanding of in vivo platelet release and blood formation. Human bone marrow acts as a source of cells required for erythropoiesis and megakaryopoeiesis. Understanding of molecular mechanism and physiology of these vital and curitial events allowed us to mimic these conditions ex vivo and to develop artificial platelet and erythroid transfusion production technologies.
Topics: Animals; Biomimetic Materials; Blood Component Transfusion; Blood Platelets; Erythrocytes; Hemorrhage; Humans; Platelet Transfusion
PubMed: 31802445
DOI: 10.1007/5584_2019_455 -
International Journal of Molecular... Oct 2020Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis,... (Review)
Review
Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis, they are emerging mediators of the immune response and implicated in a variety of pathophysiological conditions including cancer. Despite their anucleate nature, they harbor a diverse set of RNAs, which are subject to an active sorting mechanism from megakaryocytes into proplatelets and affect platelet biogenesis and function. However, sorting mechanisms are poorly understood, but RNA-binding proteins (RBPs) have been suggested to play a crucial role. Moreover, RBPs may regulate RNA translation and decay following platelet activation. In concert with other regulators, including microRNAs, long non-coding and circular RNAs, RBPs control multiple steps of the platelet life cycle. In this review, we will highlight the different RNA species within platelets and their impact on megakaryopoiesis, platelet biogenesis and platelet function. Additionally, we will focus on the currently known concepts of post-transcriptional control mechanisms important for RNA fate within platelets with a special emphasis on RBPs.
Topics: Animals; Blood Platelets; Humans; RNA Processing, Post-Transcriptional; RNA, Untranslated; RNA-Binding Proteins; Thrombopoiesis
PubMed: 33076269
DOI: 10.3390/ijms21207614 -
Methods in Molecular Biology (Clifton,... 2021The in vitro production of platelets could provide a life-saving intervention for patients that would otherwise require donor-derived platelets. Producing large numbers...
The in vitro production of platelets could provide a life-saving intervention for patients that would otherwise require donor-derived platelets. Producing large numbers of platelets in vitro from their progenitor cells, megakaryocytes, remains remarkably difficult and inefficient. Here, a human megakaryoblast leukemia cell line (MEG-01) was used to assess the maturation of megakaryocytes and to develop a new methodology for producing high numbers of platelet-like particles from mature MEG-01 cells in vitro.
Topics: Blood Platelets; Cell Culture Techniques; Cell Line, Tumor; Cell-Derived Microparticles; Fluorescent Antibody Technique; High-Throughput Screening Assays; Humans; Leukemia, Megakaryoblastic, Acute; Megakaryocytes; Microscopy, Fluorescence; Thrombopoiesis
PubMed: 33340367
DOI: 10.1007/978-1-0716-1174-6_18