Membrane budding is a major mechanism of in vivo platelet biogenesis

Potts, Kathryn; Farley, Alison; Dawson, Caleb A.; Rimes, Joel; Biben, Christine; Graaf, Carolyn de; Potts, Margaret A; Stonehouse, Olivia; Carmagnac, Amandine; Gangatirkar, Pradnya; Josefsson, Emma C.; Anttila, Casey; Amann‐Zalcenstein, Daniela; Naik, Shalin H.; Alexander, Warren S.; Hilton, Douglas J.; Hawkins, Edwin D.; Taoudi, Samir

doi:10.1084/jem.20191206

Cited by 58 publications

(59 citation statements)

References 69 publications

(106 reference statements)

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“…However, under special conditions associated with strongly increased platelet turnover, platelets can be released through megakaryocyte rupture [ 7 ]. More recently, based on the calculation of the rate of proplatelet formation required for physiological platelet replacement, it has been suggested that membrane budding, rather than proplatelet formation, supplies the majority of the platelet biomass in vivo [ 8 ]. The release of platelets in lungs by megakaryocytes entered in blood and disintegrated by the impact with the pulmonary microcirculation has also been shown, but its relevance for platelet production is a matter of controversy [ 9 ].…”

Section: Megakaryocytopoiesis and Platelet Productionmentioning

confidence: 99%

Learning the Ropes of Platelet Count Regulation: Inherited Thrombocytopenias

Bury¹,

Falcinelli²,

Gresele³

2021

JCM

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Inherited thrombocytopenias (IT) are a group of hereditary disorders characterized by a reduced platelet count sometimes associated with abnormal platelet function, which can lead to bleeding but also to syndromic manifestations and predispositions to other disorders. Currently at least 41 disorders caused by mutations in 42 different genes have been described. The pathogenic mechanisms of many forms of IT have been identified as well as the gene variants implicated in megakaryocyte maturation or platelet formation and clearance, while for several of them the pathogenic mechanism is still unknown. A range of therapeutic approaches are now available to improve survival and quality of life of patients with IT; it is thus important to recognize an IT and establish a precise diagnosis. ITs may be difficult to diagnose and an initial accurate clinical evaluation is mandatory. A combination of clinical and traditional laboratory approaches together with advanced sequencing techniques provide the highest rate of diagnostic success. Despite advancement in the diagnosis of IT, around 50% of patients still do not receive a diagnosis, therefore further research in the field of ITs is warranted to further improve patient care.

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Section: Megakaryocytopoiesis and Platelet Productionmentioning

confidence: 99%

Learning the Ropes of Platelet Count Regulation: Inherited Thrombocytopenias

Bury¹,

Falcinelli²,

Gresele³

2021

JCM

View full text Add to dashboard Cite

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“…Megakaryocytes are thought to produce platelets via a cytoskeletal-driven process, in which cytoplasmic protrusions called proplatelets extend from the BM and into the blood stream 3 , 4 . However, this model for platelet synthesis was recently challenged, because megakaryocyte membrane budding, rather than proplatelet formation, was reported to supply the majority of the platelet biomass 5 . Alternative mechanisms, such as megakaryocyte rupture, have been proposed in response to acute needs 6 , 7 .…”

Section: Introductionmentioning

confidence: 99%

The necroptotic cell death pathway operates in megakaryocytes, but not in platelet synthesis

et al. 2021

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Necroptosis is a pro-inflammatory cell death program executed by the terminal effector, mixed lineage kinase domain-like (MLKL). Previous studies suggested a role for the necroptotic machinery in platelets, where loss of MLKL or its upstream regulator, RIPK3 kinase, impacted thrombosis and haemostasis. However, it remains unknown whether necroptosis operates within megakaryocytes, the progenitors of platelets, and whether necroptotic cell death might contribute to or diminish platelet production. Here, we demonstrate that megakaryocytes possess a functional necroptosis signalling cascade. Necroptosis activation leads to phosphorylation of MLKL, loss of viability and cell swelling. Analyses at steady state and post antibody-mediated thrombocytopenia revealed that platelet production was normal in the absence of MLKL, however, platelet activation and haemostasis were impaired with prolonged tail re-bleeding times. We conclude that MLKL plays a role in regulating platelet function and haemostasis and that necroptosis signalling in megakaryocytes is dispensable for platelet production.

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“… 18 A recent study demonstrated that membrane budding also contributes to supply the platelet biomass. 19 For erythrocytes the crucial step entails expulsion of the nucleus from erythroblasts, which leads to the formation of reticulocytes, and the loss of organelles and ribosomes through autophagy/exosome-combined pathways. 20 …”

Section: Looking Inside the Bone Marrow: An Overview On The Origin Of Blood Platelets And Erythrocytes In Vivomentioning

confidence: 99%

Latest culture techniques: cracking the secrets of bone marrow to mass-produce erythrocytes and platelets <i>ex vivo

et al. 2021

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Since the dawn of medicine, scientists have carefully observed, modeled and interpreted the human body to improve healthcare. At the beginning there were drawings and paintings, now there is three-dimensional modeling. Moving from two-dimensional cultures and towards complex and relevant biomaterials, tissue-engineering approaches have been developed in order to create three-dimensional functional mimics of native organs. The bone marrow represents a challenging organ to reproduce because of its structure and composition that confer it unique biochemical and mechanical features to control hematopoiesis. Reproducing the human bone marrow niche is instrumental to answer the growing demand for human erythrocytes and platelets for fundamental studies and clinical applications in transfusion medicine. In this review, we discuss the latest culture techniques and technological approaches to obtain functional platelets and erythrocytes ex vivo. This is a rapidly evolving field that will define the future of targeted therapies for thrombocytopenia and anemia, but also a long-term promise for new approaches to the understanding and cure of hematologic diseases.

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Membrane budding is a major mechanism of in vivo platelet biogenesis

Cited by 58 publications

References 69 publications

Learning the Ropes of Platelet Count Regulation: Inherited Thrombocytopenias

Learning the Ropes of Platelet Count Regulation: Inherited Thrombocytopenias

The necroptotic cell death pathway operates in megakaryocytes, but not in platelet synthesis

Latest culture techniques: cracking the secrets of bone marrow to mass-produce erythrocytes and platelets <i>ex vivo

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