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International Journal of Molecular... Dec 2023Apoptosis signal-regulating kinase 1 (ASK1) is a serine-threonine kinase that is ubiquitously expressed in nucleated cells and is responsible for the activation of... (Review)
Review
Apoptosis signal-regulating kinase 1 (ASK1) is a serine-threonine kinase that is ubiquitously expressed in nucleated cells and is responsible for the activation of multiple mitogen-activated protein kinases (MAPK) to regulate cell stress. Activation of ASK1 via cellular stress leads to activation of downstream signaling components, activation of transcription factors, and proinflammatory cytokine production. ASK1 is also expressed in anucleate platelets and is a key player in platelet activation as it is important for signaling. Interestingly, the mechanism of ASK1 activation is cell type-dependent. In this review we will explore how ASK1 regulates a variety of cellular processes from innate immune function to thrombosis and hemostasis. We will discuss how ASK1 influences FcγRIIA-mediated platelet reactivity and how that reactivity drives platelet clearance. Furthermore, we will explore the role of ASK1 in thromboxane (TxA) generation, which highlights differences in the way ASK1 functions in mouse and human platelets.
Topics: Humans; Animals; Mice; MAP Kinase Kinase Kinase 5; Sepsis; Blood Platelets; Kinetics; Mitogen-Activated Protein Kinases
PubMed: 38203381
DOI: 10.3390/ijms25010213 -
Platelets Dec 2023Research into the natural aging process of platelets has garnered much research interest in recent years, and there have long been associations drawn between the... (Review)
Review
Research into the natural aging process of platelets has garnered much research interest in recent years, and there have long been associations drawn between the proportion of newly formed platelets in the circulation and the risk of thrombosis. However, these observations have largely been demonstrated in patient groups in which there may be underlying systemic changes that effect platelet function. Recent advances in technology have allowed in-depth analysis of differently aged platelets isolated from the peripheral blood of healthy individuals and have demonstrated that aged platelets, often referred to as senescent platelets, undergo extensive changes in the transcriptome and proteome. Ultimately, these changes result in platelets whose functions have deteriorated such that they cannot partake in hemostatic responses to the same extent as newly formed platelets. Here, we review transcriptomic and proteomic research in platelet aging in the context of health and how this research sheds light upon alterations in platelet structure and function.
Topics: Humans; Aged; Transcriptome; Proteome; Proteomics; Blood Platelets; Aging
PubMed: 37070955
DOI: 10.1080/09537104.2023.2200838 -
International Journal of Molecular... Aug 2023-negative myeloproliferative neoplasms (MPNs) are a group of hematopoietic malignancies in which somatic mutations are acquired in hematopoietic stem/progenitor cells,... (Review)
Review
-negative myeloproliferative neoplasms (MPNs) are a group of hematopoietic malignancies in which somatic mutations are acquired in hematopoietic stem/progenitor cells, resulting in an abnormal increase in blood cells in peripheral blood and fibrosis in bone marrow. Mutations in , , and are frequently found in -negative MPNs, and detecting typical mutations in these three genes has become essential for the diagnosis of -negative MPNs. Furthermore, comprehensive gene mutation and expression analyses performed using massively parallel sequencing have identified gene mutations associated with the prognosis of -negative MPNs such as , , , , and . Furthermore, single-cell analyses have partially elucidated the effect of the order of mutation acquisition on the phenotype of -negative MPNs and the mechanism of the pathogenesis of -negative MPNs. Recently, specific overexpression has been identified in megakaryocytes and platelets in -negative MPNs, which may be promising for the development of diagnostic applications. In this review, we describe the genetic mutations found in -negative MPNs, including the results of analyses conducted by our group.
Topics: Humans; Myeloproliferative Disorders; Hematopoietic Stem Cells; Megakaryocytes; Blood Platelets; Hematologic Neoplasms
PubMed: 37629188
DOI: 10.3390/ijms241613008 -
Cells Jul 2023Platelets are cellular elements that are physiologically involved in hemostasis, inflammation, thrombotic events, and various human diseases. There is a link between the... (Review)
Review
Platelets are cellular elements that are physiologically involved in hemostasis, inflammation, thrombotic events, and various human diseases. There is a link between the activation of platelets and their metabolism. Platelets possess considerable metabolic versatility. Although the role of platelets in hemostasis and inflammation is known, our current understanding of platelet metabolism in terms of substrate preference is limited. Platelet activation triggers an oxidative metabolism increase to sustain energy requirements better than aerobic glycolysis alone. In addition, platelets possess extra-mitochondrial oxidative phosphorylation, which could be one of the sources of chemical energy required for platelet activation. This review aims to provide an overview of flexible platelet metabolism, focusing on the role of metabolic compartmentalization in substrate preference, since the metabolic flexibility of stimulated platelets could depend on subcellular localization and functional timing. Thus, developing a detailed understanding of the link between platelet activation and metabolic changes is crucial for improving human health.
Topics: Humans; Blood Platelets; Glycolysis; Platelet Activation; Energy Metabolism; Inflammation
PubMed: 37443836
DOI: 10.3390/cells12131802 -
Blood Advances Oct 2023Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic...
Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic events, which are largely refractory to anticoagulation and/or antiplatelet therapy. Anticomplement therapy, however, efficiently prevents thrombotic events in PNH and aHUS, but the underlying mechanisms remain unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by adenosine 5'-diphosphate (ADP). Blockage of C3 or C5 abolished platelet activation. We found that human platelets failed to respond functionally to the anaphylatoxins C3a and C5a. Instead, complement activation did lead to prothrombotic cell activation in the whole blood when membrane attack complex (MAC)-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation, although full complement activation, which causes hemolysis, occurred. By using an established model of mismatched erythrocyte transfusions in rats, we crossvalidated these findings in vivo using the complement inhibitor OmCI and cobra venom factor. Consumptive complement activation in this animal model only led to a thrombotic phenotype when MAC-mediated cytolysis occurred. In conclusion, complement activation only induces substantial prothrombotic cell activation if terminal pathway activation culminates in MAC-mediated release of intracellular ADP. These results explain why anticomplement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.
Topics: Humans; Rats; Animals; Complement Membrane Attack Complex; Hemolysis; Erythrocytes; Complement Activation; Blood Platelets; Hemoglobinuria, Paroxysmal; Atypical Hemolytic Uremic Syndrome
PubMed: 37428869
DOI: 10.1182/bloodadvances.2023010817 -
Platelets Dec 2023Besides their proteome, platelets use, in all responses to the environmental cues, a huge and diverse family of hydrophobic and amphipathic small molecules involved in...
Besides their proteome, platelets use, in all responses to the environmental cues, a huge and diverse family of hydrophobic and amphipathic small molecules involved in structural, metabolic and signaling functions; the lipids. Studying how platelet lipidome changes modulate platelet function is an old story constantly renewed through the impressive technical advances allowing the discovery of new lipids, functions and metabolic pathways. Technical progress in analytical lipidomic profiling by top-of-the-line approaches such as nuclear magnetic resonance and gas chromatography or liquid chromatography coupled to mass spectrometry enables either large-scale analysis of lipids or targeted lipidomics. With the support of bioinformatics tools and databases, it is now possible to investigate thousands of lipids over a concentration range of several orders of magnitude. The lipidomic landscape of platelets is considered a treasure trove, not only able to expand our knowledge of platelet biology and pathologies but also to bring diagnostic and therapeutic opportunities. The aim of this commentary article is to summarize the advances in the field and to highlight what lipidomics can tell us about platelet biology and pathophysiology.
Topics: Humans; Lipidomics; Blood Platelets; Chromatography, Liquid; Computational Biology; Lipids
PubMed: 36880158
DOI: 10.1080/09537104.2023.2182180 -
Stem Cell Research Dec 2023Takenouchi-Kosaki Syndrome (TKS) is a congenital multi-organ disorder caused by the de novo missense mutation c.191A > G p. Tyr64Cys (Y64C) in the CDC42 gene. We...
Takenouchi-Kosaki Syndrome (TKS) is a congenital multi-organ disorder caused by the de novo missense mutation c.191A > G p. Tyr64Cys (Y64C) in the CDC42 gene. We previously elucidated the functional abnormalities and thrombopoietic effects of Y64C using HEK293 and MEG01 cells. In the present study, we used iPSCs derived from TKS patients to model the disease and successfully recapitulated macrothrombocytopenia, a prominent TKS phenotype. The megakaryopoietic differentiation potential of TKS-iPSCs and platelet production capacity were examined using an efficient platelet production method redesigned from existing protocols. The results obtained showed that TKS-iPSCs produced fewer hematopoietic progenitor cells, exhibited defective megakaryopoiesis, and released platelets with an abnormally low count and giant morphology. We herein report the first analysis of TKS-iPSC-derived megakaryocytes and platelets, and currently utilize this model to perform drug evaluations for TKS. Therefore, our simple yet effective differentiation method, which mimics the disease in a dish, is a feasible strategy for studying hematopoiesis and related diseases.
Topics: Humans; Induced Pluripotent Stem Cells; HEK293 Cells; Blood Platelets; Megakaryocytes; Cell Differentiation
PubMed: 37918315
DOI: 10.1016/j.scr.2023.103221 -
International Journal of Molecular... Apr 2024Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial... (Review)
Review
Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.
Topics: Humans; Thrombosis; Blood Platelets; Hemostasis; Platelet Activation; Animals; Platelet Adhesiveness; Platelet Aggregation
PubMed: 38732019
DOI: 10.3390/ijms25094800 -
Journal of Biomedical Science Sep 2023Platelets are small anucleated blood cells primarily known for their vital hemostatic role. Allogeneic platelet concentrates (PCs) collected from healthy donors are an... (Review)
Review
Platelets are small anucleated blood cells primarily known for their vital hemostatic role. Allogeneic platelet concentrates (PCs) collected from healthy donors are an essential cellular product transfused by hospitals to control or prevent bleeding in patients affected by thrombocytopenia or platelet dysfunctions. Platelets fulfill additional essential functions in innate and adaptive immunity and inflammation, as well as in wound-healing and tissue-repair mechanisms. Platelets contain mitochondria, lysosomes, dense granules, and alpha-granules, which collectively are a remarkable reservoir of multiple trophic factors, enzymes, and signaling molecules. In addition, platelets are prone to release in the blood circulation a unique set of extracellular vesicles (p-EVs), which carry a rich biomolecular cargo influential in cell-cell communications. The exceptional functional roles played by platelets and p-EVs explain the recent interest in exploring the use of allogeneic PCs as source material to develop new biotherapies that could address needs in cell therapy, regenerative medicine, and targeted drug delivery. Pooled human platelet lysates (HPLs) can be produced from allogeneic PCs that have reached their expiration date and are no longer suitable for transfusion but remain valuable source materials for other applications. These HPLs can substitute for fetal bovine serum as a clinical grade xeno-free supplement of growth media used in the in vitro expansion of human cells for transplantation purposes. The use of expired allogeneic platelet concentrates has opened the way for small-pool or large-pool allogeneic HPLs and HPL-derived p-EVs as biotherapy for ocular surface disorders, wound care and, potentially, neurodegenerative diseases, osteoarthritis, and others. Additionally, allogeneic platelets are now seen as a readily available source of cells and EVs that can be exploited for targeted drug delivery vehicles. This article aims to offer an in-depth update on emerging translational applications of allogeneic platelet biotherapies while also highlighting their advantages and limitations as a clinical modality in regenerative medicine and cell therapies.
Topics: Humans; Regenerative Medicine; Blood Platelets; Cell- and Tissue-Based Therapy; Extracellular Vesicles; Hematopoietic Stem Cell Transplantation
PubMed: 37704991
DOI: 10.1186/s12929-023-00972-w -
Platelets Dec 2023The field of proteomics and its application to platelet biology, is rapidly and promisingly developing. Platelets (and megakaryocytes) are postulated as biosensors of... (Review)
Review
The field of proteomics and its application to platelet biology, is rapidly and promisingly developing. Platelets (and megakaryocytes) are postulated as biosensors of health and disease, and their proteome poses as a tool to identify the specific health-disease hallmarks. Furthermore, the clinical management of certain pathologies where platelets are active players demands the development of alternative treatments, such is the case in patients where the balance thrombosis-bleeding is compromised, and a proteomics approach might aid at the identification of novel targets. Hereby, the mouse and human platelet proteomes and secretomes from public databases are compared, which shows that human and mouse platelets share a highly conserved proteome, considering identified proteins, and most importantly, their relative abundance. These supports, also interspecies wise, the use of the proteomics tool in the field, substantiated by a growing number of clinically relevant studies in humans or preclinical models. While the study of platelets through proteomics seems accessible and direct (. noninvasive blood sampling, enucleated), there are some points of concern regarding the quality control of samples for such proteomics studies. Importantly, the quality of the generated data is improving over the years, which will allow cross-study comparisons. In parallel, the application of proteomics to the megakaryocyte compartment has a promising but long journey ahead. We foresee and encourage the application of platelet proteomics for diagnostic/prognostic purposes even beyond hematopoiesis and transfusion medicine, and as a tool that will procure the improvement of current therapies and the development of alternative treatment options.
Topics: Humans; Animals; Mice; Blood Platelets; Proteomics; Proteome; Megakaryocytes
PubMed: 37283127
DOI: 10.1080/09537104.2023.2220415