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Circulation Research Jan 2022Classically, platelets have been described as the cellular blood component that mediates hemostasis and thrombosis. This important platelet function has received... (Review)
Review
Classically, platelets have been described as the cellular blood component that mediates hemostasis and thrombosis. This important platelet function has received significant research attention for >150 years. The immune cell functions of platelets are much less appreciated. Platelets interact with and activate cells of all branches of immunity in response to pathogen exposures and infection, as well as in response to sterile tissue injury. In this review, we focus on innate immune mechanisms of platelet activation, platelet interactions with innate immune cells, as well as the intersection of platelets and adaptive immunity. The immune potential of platelets is dependent in part on their megakaryocyte precursor providing them with the molecular composition to be first responders and immune sentinels in initiating and orchestrating coordinated pathogen immune responses. There is emerging evidence that extramedullary megakaryocytes may be immune differentiated compared with bone marrow megakaryocytes, but the physiological relevance of immunophenotypic differences are just beginning to be explored. These concepts are also discussed in this review. The immune functions of the megakaryocyte/platelet lineage have likely evolved to coordinate the need to repair a vascular breach with the simultaneous need to induce an immune response that may limit pathogen invasion once the blood is exposed to an external environment.
Topics: Adaptive Immunity; Animals; Blood Platelets; Humans; Immunity, Innate; Megakaryocytes
PubMed: 35050690
DOI: 10.1161/CIRCRESAHA.121.319821 -
Arteriosclerosis, Thrombosis, and... Jul 2019Megakaryocytes are hematopoietic cells, which are responsible for the production of blood platelets. The traditional view of megakaryopoiesis describes the cellular... (Review)
Review
Megakaryocytes are hematopoietic cells, which are responsible for the production of blood platelets. The traditional view of megakaryopoiesis describes the cellular journey from hematopoietic stem cells, through a hierarchical series of progenitor cells, ultimately to a mature megakaryocyte. Once mature, the megakaryocyte then undergoes a terminal maturation process involving multiple rounds of endomitosis and cytoplasmic restructuring to allow platelet formation. However, recent studies have begun to redefine this hierarchy and shed new light on alternative routes by which hematopoietic stem cells are differentiated into megakaryocytes. In particular, the origin of megakaryocytes, including the existence and hierarchy of megakaryocyte progenitors, has been redefined, as new studies are suggesting that hematopoietic stem cells originate as megakaryocyte-primed and can bypass traditional lineage checkpoints. Overall, it is becoming evident that megakaryopoiesis does not only occur as a stepwise process, but is dynamic and adaptive to biological needs. In this review, we will reexamine the canonical dogmas of megakaryopoiesis and provide an updated framework for interpreting the roles of traditional pathways in the context of new megakaryocyte biology. Visual Overview- An online visual overview is available for this article.
Topics: Bone Marrow Cells; Cell Communication; Cell Cycle; Cell Differentiation; Cell Lineage; Hematopoietic Stem Cells; Humans; Inflammation; Megakaryocytes; Signal Transduction; Thrombopoiesis; Thrombopoietin; Transcription Factors
PubMed: 31043076
DOI: 10.1161/ATVBAHA.119.312129 -
Nature Communications Oct 2020Thrombosis leads to platelet activation and subsequent degradation; therefore, replenishment of platelets from hematopoietic stem/progenitor cells (HSPCs) is needed to...
Thrombosis leads to platelet activation and subsequent degradation; therefore, replenishment of platelets from hematopoietic stem/progenitor cells (HSPCs) is needed to maintain the physiological level of circulating platelets. Platelet-derived microparticles (PMPs) are protein- and RNA-containing vesicles released from activated platelets. We hypothesized that factors carried by PMPs might influence the production of platelets from HSPCs, in a positive feedback fashion. Here we show that, during mouse acute liver injury, the density of megakaryocyte in the bone marrow increases following an increase in circulating PMPs, but without thrombopoietin (TPO) upregulation. In vitro, PMPs are internalized by HSPCs and drive them toward a megakaryocytic fate. Mechanistically, miR-1915-3p, a miRNA highly enriched in PMPs, is transported to target cells and suppresses the expression levels of Rho GTPase family member B, thereby inducing megakaryopoiesis. In addition, direct injection of PMPs into irradiated mice increases the number of megakaryocytes and platelets without affecting TPO levels. In conclusion, our data reveal that PMPs have a role in promoting megakaryocytic differentiation and platelet production.
Topics: Animals; Base Sequence; Blood Platelets; Cell Differentiation; Cell Line; Cell-Derived Microparticles; Endocytosis; Gene Expression Profiling; Humans; Liver; Male; Megakaryocytes; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs; Polyploidy; rhoB GTP-Binding Protein
PubMed: 33009394
DOI: 10.1038/s41467-020-18802-0 -
The Journal of Cell Biology Jun 2013Circulating blood platelets are specialized cells that prevent bleeding and minimize blood vessel injury. Large progenitor cells in the bone marrow called megakaryocytes... (Review)
Review
Circulating blood platelets are specialized cells that prevent bleeding and minimize blood vessel injury. Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets. Given the need for platelets in many pathological situations, understanding how this process occurs is an active area of research with important clinical applications.
Topics: Animals; Blood Platelets; Cell Differentiation; Cytoskeleton; Humans; Megakaryocytes
PubMed: 23751492
DOI: 10.1083/jcb.201304054 -
Nature Jan 2018Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and...
Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and multipotent progenitor cells sitting at the very top. Multiple models have been proposed as to what the earliest lineage choices are in these primitive haematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them. Given that the bulk of studies addressing lineage outcomes have been performed in the context of haematopoietic transplantation, current models of lineage branching are more likely to represent roadmaps of lineage potential than native fate. Here we use transposon tagging to clonally trace the fates of progenitors and stem cells in unperturbed haematopoiesis. Our results describe a distinct clonal roadmap in which the megakaryocyte lineage arises largely independently of other haematopoietic fates. Our data, combined with single-cell RNA sequencing, identify a functional hierarchy of unilineage- and oligolineage-producing clones within the multipotent progenitor population. Finally, our results demonstrate that traditionally defined long-term haematopoietic stem cells are a significant source of megakaryocyte-restricted progenitors, suggesting that the megakaryocyte lineage is the predominant native fate of long-term haematopoietic stem cells. Our study provides evidence for a substantially revised roadmap for unperturbed haematopoiesis, and highlights unique properties of multipotent progenitors and haematopoietic stem cells in situ.
Topics: Animals; Cell Lineage; Clone Cells; Female; Hematopoiesis; Hematopoietic Stem Cells; Male; Megakaryocytes; Mice; Multipotent Stem Cells; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 29323290
DOI: 10.1038/nature25168 -
Cell Jul 2018The ex vivo generation of platelets from human-induced pluripotent cells (hiPSCs) is expected to compensate donor-dependent transfusion systems. However, manufacturing...
The ex vivo generation of platelets from human-induced pluripotent cells (hiPSCs) is expected to compensate donor-dependent transfusion systems. However, manufacturing the clinically required number of platelets remains unachieved due to the low platelet release from hiPSC-derived megakaryocytes (hiPSC-MKs). Here, we report turbulence as a physical regulator in thrombopoiesis in vivo and its application to turbulence-controllable bioreactors. The identification of turbulent energy as a determinant parameter allowed scale-up to 8 L for the generation of 100 billion-order platelets from hiPSC-MKs, which satisfies clinical requirements. Turbulent flow promoted the release from megakaryocytes of IGFBP2, MIF, and Nardilysin to facilitate platelet shedding. hiPSC-platelets showed properties of bona fide human platelets, including circulation and hemostasis capacities upon transfusion in two animal models. This study provides a concept in which a coordinated physico-chemical mechanism promotes platelet biogenesis and an innovative strategy for ex vivo platelet manufacturing.
Topics: Bioreactors; Blood Platelets; Cell Culture Techniques; Humans; Hydrodynamics; Induced Pluripotent Stem Cells; Megakaryocytes; Thrombopoiesis
PubMed: 30017246
DOI: 10.1016/j.cell.2018.06.011 -
Experimental Hematology Feb 2022Mature megakaryocytes, the platelet precursors, originate from hematopoietic stem cell progenitors, which, once committed to this lineage, undergo endomitosis leading to... (Review)
Review
Mature megakaryocytes, the platelet precursors, originate from hematopoietic stem cell progenitors, which, once committed to this lineage, undergo endomitosis leading to polyploidization. The process entails repeated rounds of DNA replication without cell division, yielding polyploid cells. Supporting the cell's developmental process and various cellular functions are integrin receptors, a conduit of communication between the extracellular environment and the cell actin cytoskeleton. Integrins are heterodimers of α and β subunits, where different combinations of the known 18 α and 8 β subunits confer specificity to the receptor. Integrin ligands range from extracellular matrices through soluble ligands, infectious agents, and counterreceptors, to cells. In this review, we describe the different integrins expressed on bone marrow megakaryocytes and their attributed roles in lineage development and cellular functions, including adhesion, spreading, proplatelet formation, and functional interaction with other cells. Pathologies associated with dysregulated megakaryocyte integrin expression are also reviewed.
Topics: Animals; Blood Platelets; Cell Adhesion; Humans; Integrins; Megakaryocytes; Thrombopoiesis
PubMed: 34910941
DOI: 10.1016/j.exphem.2021.11.007 -
Blood Mar 2016Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product... (Review)
Review
Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product for an individual's lifetime. Hematologic defects that can be corrected with an allogeneic bone marrow transplant can theoretically also be treated with gene replacement therapy. Because some genetic disorders affect distinct cell lineages, researchers are utilizing HSC gene transfer techniques using lineage-specific endogenous gene promoters to confine transgene expression to individual cell types (eg, ITGA2B for inherited platelet defects). HSCs appear to be an ideal target for platelet gene therapy because they can differentiate into megakaryocytes which are capable of forming several thousand anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury. Platelets play an essential role in other biological processes (immune response, angiogenesis) as well as diseased states (atherosclerosis, cancer, thrombosis). Thus, recent advances in genetic manipulation of megakaryocytes could lead to new and improved therapies for treating a variety of disorders. In summary, genetic manipulation of megakaryocytes has progressed to the point where clinically relevant strategies are being developed for human trials for genetic disorders affecting platelets. Nevertheless, challenges still need to be overcome to perfect this field; therefore, strategies to increase the safety and benefit of megakaryocyte gene therapy will be discussed.
Topics: Animals; Genetic Therapy; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Integrin alpha2; Megakaryocyte Progenitor Cells; Megakaryocytes; Transgenes
PubMed: 26787735
DOI: 10.1182/blood-2015-07-607937 -
Seminars in Hematology Jul 2010The process of megakaryopoiesis and platelet production is complex, with the potential for regulation at multiple stages. Megakaryocytes are derived from the... (Review)
Review
The process of megakaryopoiesis and platelet production is complex, with the potential for regulation at multiple stages. Megakaryocytes are derived from the hematopoietic stem cell through successive lineage commitment steps, and they undergo a unique maturation process that includes polyploidization, development of an extensive internal demarcation membrane system, and finally formation of pro-platelet processes. Platelets are shed from these processes into vascular sinusoids within the bone marrow. Megakaryocyte differentiation is regulated both positively and negatively by transcription factors and cytokine signaling. Thrombopoietin (TPO) is the most important hematopoietic cytokine for platelet production. Clinically, acquired and inherited mutations affecting megakaryocytic transcription factors and thrombopoietin signaling have been identified in disorders of thrombocytopenia and thrombocytosis.
Topics: Humans; Megakaryocytes; Signal Transduction; Thrombopoietin
PubMed: 20620431
DOI: 10.1053/j.seminhematol.2010.03.001 -
Arteriosclerosis, Thrombosis, and... Jun 2020Anucleate platelets, long viewed as merely cell fragments with a limited repertoire of rapid-acting hemostatic functions, are now recognized to have a complex and... (Comparative Study)
Comparative Study Review
Anucleate platelets, long viewed as merely cell fragments with a limited repertoire of rapid-acting hemostatic functions, are now recognized to have a complex and dynamic transcriptome mirroring that of many nucleated cells. The field of megakaryocyte and platelet transcriptomics has been rapidly growing, particularly with the advent of newer technologies such as next-generation RNA-sequencing. Studies interrogating the megakaryocyte and platelet transcriptome have led to a number of key insights into human health and disease. In this brief focused review, we will discuss some of the recent discoveries made through transcriptome analysis of megakaryocytes and platelets. We will also highlight the utility of integrating ribosome footprint analysis to augment discoveries. Both bulk and single-cell sequencing approaches will be reviewed, along with comparative studies between human and murine platelets under basal healthy settings and during acute systemic inflammatory diseases.
Topics: Adult; Aged; Aging; Animals; Blood Platelets; Cross-Sectional Studies; Gene Expression Profiling; HIV Infections; Health Status; Hemostasis; High-Throughput Nucleotide Sequencing; Humans; Longitudinal Studies; Megakaryocytes; Mice; Sequence Analysis, RNA; Single-Cell Analysis; Species Specificity
PubMed: 32295424
DOI: 10.1161/ATVBAHA.119.313280