The biogenesis of platelets from megakaryocyte proplatelets

Abstract

Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. The production of platelets by megakaryocytes requires an intricate series of remodeling events that result in the release of thousands of platelets from a single megakaryocyte. Abnormalities in this process can result in clinically significant disorders. Thrombocytopenia (platelet counts less than 150,000/µl) can lead to inadequate clot formation and increased risk of bleeding, while thrombocythemia (platelet counts greater than 600,000/µl) can heighten the risk for thrombotic events, including stroke, peripheral ischemia, and myocardial infarction. This Review will describe the process of platelet assembly in detail and discuss several disorders that affect platelet production. Platelet formationMegakaryocyte development. Megakaryocytes are rare myeloid cells (constituting less than 1% of these cells) that reside primarily in the bone marrow (1) but are also found in the lung and peripheral blood. In early development, before the marrow cavities have enlarged sufficiently to support blood cell development, megakaryopoiesis occurs within the fetal liver and yolk sac. Megakaryocytes arise from pluripotent HSCs that develop into 2 types of precursors, burst-forming cells and colony-forming cells, both of which express the CD34 antigen (2). Development of both cell types continues along an increasingly restricted lineage culminating in the formation of megakaryocyte precursors that develop into megakaryocytes (1). Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is currently the only known cytokine required for megakaryocytes to maintain a constant platelet mass (3). TPO is thought to act in conjunction with other factors, including IL-3, IL-6, and IL-11, although these cytokines are not essential for megakaryocyte maturation (4).Megakaryocytes tailor their cytoplasm and membrane systems for platelet biogenesis. Before a megakaryocyte has the capacity to release platelets, it enlarges considerably to an approximate diameter of 100 µm and fills with high concentrations of ribosomes that facilitate the production of platelet-specific proteins (5). Cellular enlargement is mediated by multiple rounds of endomitosis, a process that amplifies the DNA by as much as 64-fold (6-9). TPO, which binds to the c-Mpl receptor, promotes megakaryocyte endomitosis. During endomitosis, chromosomes replicate and the nuclear envelope breaks down. Although interconnected mitotic spindles assemble, the normal mitotic cycle is arrested during anaphase B. The spindles fail to separate, and both telophase and cytokinesis are bypassed. Nuclear envelope reformation (10, 11) results in a polyploid, multilobed nucleus with DNA contents ranging from 4N up to 128N within each megakaryocyte (12).In addition to expansion of DNA, megakaryocytes experience significant maturation as internal membrane systems, granules, and organelles are assembled in bulk during their development. In particular, there is th...

Platelet bioreactor-on-a-chip

“…on April 2, 2019. by guest www.bloodjournal.org From has been that in vitro cultures extend proPLTs at a significantly slower rate than what has been observed in vivo. Application of physiological shear stress in our microfluidic bioreactor increased the proPLT extension rate by an order of magnitude above static culture controls 41 (supplemental Figure 6I) to ;30 mm/min (Figure 3E), which agree with physiological estimates of proPLT extension rates from intravital microscopy studies in living mice 11 and support increased PLT production in vitro.…”

Bcl-2 family proteins are essential for platelet survival

“…The similarities between platelet biogenesis from megakaryocytes and apoptosis include membrane blebbing, membrane condensation, DNA fragmentation, cell shrinkage, and ultimately the formation of apoptotic bodies. 5,6 The consequence of this apoptotic process is that each mature megakaryocyte fragments into thousands of platelets. 5 Once released into the circulation, platelets rapidly age with a halflife of 4-5 days.…”

Plaquetas: Papéis tradicionais e não tradicionais na hemostasia, na inflamação e no câncer

“…As técnicas de imagem com matriz fluorescente e sondas quimioluminescentes permitem o d) Vasos sanguíneos 15 sinusoidais: pequenos vasos sanguíneos similares a capilares, porém com pequenas aberturas de comunicação com o endotélio. Trombopoetina 13 : citocina que influencia a diferenciação de megacariócitos e como consequência atua no processo de trombopoiese na formação de PPs. Forças de cisalhamento 15 : resultado do fluxo sanguíneo diferencial, ou seja a velocidade do fluxo de sangue é mais elevada no centro dos vasos e diminui no sentido da parede do vaso.…”

“…Há evidências que o pulmão é um reservatório de megacariócitos, além de ser um local de processamento de PPs. Megacariócitos são descritos como cé-lulas poliplóides e que se acumulam em pulmões de humanos e roedores 13,14 .…”