Ultrastructural characterization of maturation, platelet release, and senescence of human cultured megakaryocytes

Falcieri, Elisabetta; Bassini, Alessandra; Pierpaoli, Sabina; Luchetti, Francesca; Zamai, Loris; Vitale, Marco; Guidotti, Lia; Zauli, Giorgio

doi:10.1002/(sici)1097-0185(20000101)258:1<90::aid-ar10>3.0.co;2-g

Cited by 55 publications

(35 citation statements)

References 28 publications

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“…Recent studies attempted to investigate the relationship existing between megakaryocyte maturation, apoptosis, and proplatelet formation in culture of CD34 ϩ -derived megakaryocytes. 7,8 Although unable to investigate in depth the subordination of events, this study showed that apoptosis occurred predominantly in mature megakaryocytes rather than in immature megakaryoblasts. Moreover, the kinetics of platelet release into the culture supernatants corresponded to the onset of apoptosis in these cells.…”

Section: Introductionmentioning

confidence: 76%

BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation

Kaluzhny

Sun

et al. 2002

Blood

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Fragmentation of polyploid megakaryocytes into platelets has great relevance for blood homeostasis. Apoptotic cell death is a highly regulated genetic program, which has been observed in mature megakaryocytes fragmenting into platelets. The antiapoptotic protein BclxL has been reported as up-regulated during megakaryocytic differentiation in vitro, but absent during late megakaryopoiesis. Our study focused on examining BclxL levels in megakaryocytes in vivo and in assessing the effect of its overexpression in transgenic mice (via the platelet factor 4 [PF4] promoter) on megakaryocyte development and platelet fragmentation. Interestingly, in the wild-type and less in PF4-driven transgenic mice, BclxL was not detected in a fraction of the large mature megakaryocytes, suggesting a regulation on the protein level. BclxL overexpression was associated with a moderate increase in megakaryocyte number, with no significant change in ploidy level or platelet counts. When the mice were challenged by induction of immune thrombocytopenia, the rate of platelet recovery was significantly slower in the transgenic mice as compared with controls. Moreover, proplatelet formation in vitro by transgenic megakaryocytes was limited. Transgenic megakaryocytes displayed poorly developed platelet demarcation membranes and cell margin extensions. Our study indicates that regulated expression of BclxL in megakaryocytes is important for the development of cells with a high potential to fragment into platelets.

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Section: Introductionmentioning

confidence: 76%

BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation

Kaluzhny

Sun

et al. 2002

Blood

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“…However, it is thought that a specialized apoptotic process may lead to platelet assembly and release. Apoptosis has been described in megakaryocytes (56) and found to be more prominent in mature megakaryocytes as opposed to immature cells (57,58). A number of apoptotic factors, both proapoptotic and antiapoptotic, have been identified in megakaryocytes (reviewed in ref.…”

Section: Figurementioning

confidence: 99%

The biogenesis of platelets from megakaryocyte proplatelets

Patel¹

2005

Journal of Clinical Investigation

487

406

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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...

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“…Platelets are anucleate circulating cells that are major players in the process of hemostasis and thrombosis (1,2). Platelets are produced from megakaryocytes and released into circulation, where they have a defined life span of 7-10 days in human (4 -5 days in mouse), following which they are selectively cleared by the reticuloendothelial system (3).…”

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confidence: 99%

Regulatory Role of Proteasome in Determination of Platelet Life Span

Nayak

Kulkarni

Dash

2013

Journal of Biological Chemistry

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Background:The molecular players regulating platelet life span are largely unexplored. Results: Proteasome inhibition induced apoptotic changes in platelets associated with a rise in active Bax and significant drop in platelet life span. Conclusion: Proteasome plays a crucial role in delimiting platelet life span through constitutive elimination of the conformationally active Bax. Significance: The findings bear relevance in clinical settings where proteasome is therapeutically inhibited.

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Ultrastructural characterization of maturation, platelet release, and senescence of human cultured megakaryocytes

Cited by 55 publications

References 28 publications

BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation

BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation

The biogenesis of platelets from megakaryocyte proplatelets

Regulatory Role of Proteasome in Determination of Platelet Life Span

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