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Circulation Research Apr 2024While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The...
BACKGROUND
While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The physiological implications of these constant transient interactions are poorly understood. Activated platelets induce and amplify immune responses, but platelets may also maintain immune homeostasis in healthy conditions, including maintaining vascular integrity and T helper cell differentiation, meaning that platelets are central to both immune responses and immune quiescence. Clinical data have shown an association between low platelet counts (thrombocytopenia) and immune dysfunction in patients with sepsis and extracorporeal membrane oxygenation, further implicating platelets as more holistic immune regulators, but studies of platelet immune functions in nondisease contexts have had limited study.
METHODS
We used in vivo models of thrombocytopenia and in vitro models of platelet and monocyte interactions, as well as RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing), to mechanistically determine how resting platelet and monocyte interactions immune program monocytes.
RESULTS
Circulating platelets and monocytes interact in a CD47-dependent manner to regulate monocyte metabolism, histone methylation, and gene expression. Resting platelet-monocyte interactions limit TLR (toll-like receptor) signaling responses in healthy conditions in an innate immune training-like manner. In both human patients with sepsis and mouse sepsis models, thrombocytopenia exacerbated monocyte immune dysfunction, including increased cytokine production.
CONCLUSIONS
Thrombocytopenia immune programs monocytes in a manner that may lead to immune dysfunction in the context of sepsis. This is the first demonstration that sterile, endogenous cell interactions between resting platelets and monocytes regulate monocyte metabolism and pathogen responses, demonstrating platelets to be immune rheostats in both health and disease.
Topics: Mice; Animals; Humans; Monocytes; Thrombocytopenia; Blood Platelets; Immunity; Sepsis; Platelet Activation
PubMed: 38456277
DOI: 10.1161/CIRCRESAHA.123.323662 -
Current Opinion in Hematology May 2024Thrombo-inflammation is a multifaceted pathologic process involving various cells such as platelets, neutrophils, and monocytes. In recent years, microRNAs have been... (Review)
Review
PURPOSE OF REVIEW
Thrombo-inflammation is a multifaceted pathologic process involving various cells such as platelets, neutrophils, and monocytes. In recent years, microRNAs have been consistently implicated as regulators of these cells.
RECENT FINDINGS
MicroRNAs play a regulatory role in several platelet receptors that have recently been identified as contributing to thrombo-inflammation and neutrophil extracellular trap (NET) formation. In addition, a growing body of evidence has shown that several intracellular and extracellular microRNAs directly promote NET formation.
SUMMARY
Targeting microRNAs is a promising therapeutic approach to control thrombosis in patients with both infectious and noninfectious inflammatory diseases. Future research efforts should focus on elucidating the specific roles of microRNAs in thrombo-inflammation and translating these findings into tangible benefits for patients.
Topics: Humans; MicroRNAs; Blood Platelets; Thrombosis; Inflammation; Neutrophils; Extracellular Traps
PubMed: 38277182
DOI: 10.1097/MOH.0000000000000803 -
Trends in Endocrinology and Metabolism:... Sep 2023Mitochondria operate as hubs of cellular metabolism that execute important regulatory functions. Damaged/dysfunctional mitochondria are recognized as major pathogenic... (Review)
Review
Mitochondria operate as hubs of cellular metabolism that execute important regulatory functions. Damaged/dysfunctional mitochondria are recognized as major pathogenic contributors to many common human diseases. Assessment of mitochondrial function relies upon invasive tissue biopsies; peripheral blood cells, specifically platelets, have emerged as an ideal candidate for mitochondrial function assessment. Accessibility and documented pathology-related dysfunction have prompted investigation into the role of platelets in disease, the contribution of platelet mitochondria to pathophysiology, and the capacity of platelets to reflect systemic mitochondrial health. Platelet mitochondrial bioenergetics are being investigated in neurodegenerative and cardiopulmonary diseases, infection, diabetes, and other (patho)physiological states such as aging and pregnancy. Early findings support the use of platelets as a biomarker for mitochondrial functional health.
Topics: Humans; Energy Metabolism; Mitochondria; Blood Platelets; Biomarkers; Liquid Biopsy
PubMed: 37414716
DOI: 10.1016/j.tem.2023.06.004 -
Circulation Research Jan 2024
Topics: Mitochondrial Dynamics; Blood Platelets; Megakaryocytes; Hemostasis; Platelet Activation
PubMed: 38236952
DOI: 10.1161/CIRCRESAHA.123.323867 -
International Journal of Molecular... Jul 2023Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis,... (Review)
Review
Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs in the blood of lung cancer patients has been associated with tumor growth, invasion, angiogenesis and metastasis, which correlate with disease progression and decreased survival times. The final section of the review addresses, firstly, the role of cancer-related platelet activation and thrombosis in the pathogenesis of secondary cardiovascular disorders and the associated mortality, particularly in lung cancer, which is second only to disease progression; secondly, the review addresses the potential role of antiplatelet agents in the adjunctive therapy of cancer.
Topics: Humans; Blood Platelets; Cell-Derived Microparticles; Thrombosis; Lung Neoplasms; Carcinogenesis; Disease Progression
PubMed: 37569299
DOI: 10.3390/ijms241511927 -
Platelets Dec 2023Various modifications of proteins and the resulting proteoforms of a protein can associate with many diseases and are also significantly involved in the rapid regulation...
Various modifications of proteins and the resulting proteoforms of a protein can associate with many diseases and are also significantly involved in the rapid regulation of hemostasis and thrombosis. For example, the release of prostacyclin from the intact endothelium and the consequent following phosphorylation of VASP in platelets is a post-translational regulation to keep them in a quiescent state. In Alzheimer's disease, proteoforms arise from the altered cleavage of the amyloid precursor protein, which finally causes amyloid plaques in the brain. This changed processing of the amyloid precursor protein can also be detected in platelets, making them an attractive source of biomarkers for this neurodegenerative disease. Age-related or prothrombotic disorders can have multiple origins, including genomic, transcriptional, and translational factors, which together can be mapped at the proteome level. Hence, recording these dynamic protein changes under physiological and pathophysiological conditions is paramount in platelet proteomics. To effectively study diseases through platelet proteomics, it is crucial to consider platelets' primary regulatory mechanism and thoroughly evaluate the disparities between the two leading proteomics technologies, top-down and bottom-up approaches. This commentary provides insights into the differences between these two technologies, which are particularly noticeable in detecting the different proteoforms of a protein.
Topics: Humans; Proteomics; Neurodegenerative Diseases; Amyloid beta-Protein Precursor; Blood Platelets; Protein Processing, Post-Translational; Proteome
PubMed: 37272536
DOI: 10.1080/09537104.2023.2220046 -
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 -
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 -
Current Opinion in Hematology Jan 2024This review highlights how the perception of platelet function is evolving based on recent insights into platelet mechanobiology. (Review)
Review
PURPOSE OF REVIEW
This review highlights how the perception of platelet function is evolving based on recent insights into platelet mechanobiology.
RECENT FINDINGS
The mechanosensitive ion channel Piezo1 mediates activation of free-flowing platelets under conditions of flow acceleration through mechanisms independent of adhesion receptors and classical activation pathways. Interference with the initiation of platelet migration or with the phenotypic switch of migrating platelets to a procoagulant state aggravates inflammatory bleeding. Mechanosensing of biochemical and biophysical microenvironmental cues during thrombus formation feed into platelet contractile force generation. Measurements of single platelet contraction and bulk clot retraction show promise to identify individuals at risk for hemorrhage.
SUMMARY
New findings unravel novel mechanotransduction pathways and effector functions in platelets, establishing mechanobiology as a pivotal component of platelet function. These insights highlight limitations of existing treatments and offer new potential therapeutic approaches and diagnostic avenues based on mechanobiological principles. Further extensive research is required to distinguish between core hemostatic and pathological mechanisms influenced by platelet mechanosensing.
Topics: Humans; Mechanotransduction, Cellular; Blood Platelets; Hemostasis; Thrombosis; Platelet Activation
PubMed: 37846561
DOI: 10.1097/MOH.0000000000000788 -
The American Journal of Sports Medicine Sep 2023Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease among the aged population. However, current treatments for OA are limited to alleviating...
BACKGROUND
Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease among the aged population. However, current treatments for OA are limited to alleviating symptoms, with no therapies that prevent and regenerate cartilage deterioration.
PURPOSE
To assess the effects of platelet-derived exosomes (Plt-exos) on OA and then to explore the potential molecular mechanism.
STUDY DESIGN
Controlled laboratory study.
METHODS
Exosomes derived from human apheresis platelets were isolated and identified. The effects of Plt-exos in protecting chondrocytes under interleukin 1β stimulation were evaluated by analyzing the proliferation and migration in human primary chondrocytes. RNA sequencing was later performed in vitro for primary chondrocytes to reveal the underlying mechanisms of Plt-exo treatment. Anterior cruciate ligament transection was used to construct an OA mice model, and intra-articular injection of Plt-exos was given once a week for 6 weeks. Mice were sacrificed 4 weeks after the last injection. Histologic and immunohistochemistry staining and micro-computed tomography analysis were performed to assess alterations of articular cartilage and subchondral bone.
RESULTS
Plt-exos significantly promoted proliferation and migration of chondrocytes within a dose-dependent manner, as well as dramatically promoted cartilage regeneration and attenuated abnormal tibial subchondral bone remodeling, thus slowing the progression of OA. After being treated with Plt-exos, 1797 genes were differentially expressed in chondrocytes (923 upregulated and 874 downregulated genes). Functional enrichment results and hub genes were mainly involved in anti-inflammatory effects, mediating cell adhesion, stimulating cartilage repair, promoting anabolism, and inhibiting catabolism.
CONCLUSION
Our results demonstrated that Plt-exos promoted chondrocyte proliferation and migration in vitro, as well as attenuated cartilage degeneration, improved the microarchitecture of subchondral bone, and retarded OA progression in vivo.
CLINICAL RELEVANCE
Our study illustrated that the administered Plt-exos could alleviate knee OA by attenuating cartilage degeneration and subchondral bone loss, possibly serving as a novel promising treatment for OA in the future.
Topics: Humans; Mice; Animals; Aged; Osteoarthritis, Knee; Exosomes; X-Ray Microtomography; Blood Platelets; Cartilage Diseases; Cartilage, Articular; Chondrocytes
PubMed: 37551685
DOI: 10.1177/03635465231188122