Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets
Emma C. JosefssonChloé JamesKatya J. HenleyMarlyse A. DebrincatKelly L. RogersMark R. DowlingM. J. D. WhiteElizabeth KruseRachael M. LaneSarah EllisPaquita NurdenKylie D. MasonLorraine A. O’ReillyAndrew W. RobertsDonald MetcalfDavid C.S. HuangBenjamin T. Kile
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Abstract:
It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-x(L) resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak(-/-) Bax(-/-) hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.Keywords:
Thrombopoiesis
Staurosporine
Megakaryocytopoiesis
Thrombocytopenia was induced in rabbit by a single injection of anti-platelet serum. The circulating platelet number and concomitant mean platelet volume were measured 6 h after the injection and daily thereafter. The megakaryocyte nuclear DNA content was measured in control rabbits and after 2 h and 24 h of thrombocytopenia respectively. The observed recovery of circulating platelet number is used to construct the variation of platelet destruction rate and platelet production rate with time during thrombocytopenia. The observed rebound thrombocytosis is explained by using a balance equation of these two rates. Platelet production is linked to the megakaryocyte by physical fragmentation theory and an explanation of the observed variation of mean platelet volume is used to obtain an estimated bleeding time and circulating platelet biomass during recovery from thrombocytopenia. An interpretation is given of the homeostatic control of megakaryocytopoiesis and thrombopoiesis.
Thrombopoiesis
Megakaryocytopoiesis
Mean platelet volume
Thrombocytosis
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The in vivo effect of human platelet factor 4 (PF4) on murine megakaryocytopoiesis and thrombopoiesis was studied. Administration of PF4 induced a dose-dependent decrease in the numbers of megakaryocytes and their progenitor cells (CFU-MK), continuing for 1 week after the injection. However, the size of megakaryocytes and their colonies was not changed following PF4 injection. Platelet levels were significantly decreased at days 3-4. The number of CFU-GM was decreased at days 1-2. White blood cells and hemoglobin were unaffected by PF4. These data indicate that PF4 inhibits megakaryocyte and platelet production in vivo by acting on the early stage of megakaryocyte development.
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Megakaryocytopoiesis
Ex vivo
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Megakaryocytopoiesis
Thrombopoiesis
Mean platelet volume
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At least two classes of human megakaryocyte progenitor cells have been identified: the burst-forming unit megakaryocyte (BFU-MK) and the colony-forming unit megakaryocyte (CFU-MK). The BFU-MK is the most primitive progenitor cell committed to the megakaryocytic lineage. The CFU-MK appears to be a more differentiated megakaryocyte progenitor cell and is thought to be ultimately a descendant of the BFU-MK. A number of recombinant cytokines have recently been shown to be able to promote megakaryocyte colony formation in vitro. Recombinant GM-CSF and IL-3, in particular, have the ability to promote both CFU-MK- and BFU-MK-derived colony stimulatory formation. The activities of these two cytokines on in vitro megakaryocytopoiesis are also additive. Recent results of clinical trials in both primates and humans, in which these glycoproteins were administered in vivo, suggest that these cytokines, both alone and in combination, can enhance in vivo thrombopoiesis and therefore may be potentially useful in the treatment of thrombocytopenic disorders.
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Progenitor
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Megakaryocytopoiesis
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Animals with hereditary abnormalities of hematopoiesis are quite useful in the study of regulatory pathways of megakaryocytopoiesis and platelet formation. Seven such animal models are analyzed here. The Wistar Furth rat has been recently discovered to have reduced platelet number, but large mean platelet volume, and is, therefore, a model of hereditary macrothrombocytopenia. Study of the Wistar Furth rat may help to elucidate the process of platelet formation. Two mouse mutants the S1/S1d and W/Wv, have macrocytic anemia with reduced megakaryocyte number, but normal platelet count. In these mice, the platelet count is maintained by increased platelet production per megakaryocyte. These models demonstrate that factors other than platelet level are monitored in the feedback regulation of megakaryocytopoiesis and platelet production, and further study should lead to a better understanding of the regulation of megakaryocyte size. The Belgrade rat has severe microcytic anemia with decreased megakaryocyte number. Megakaryocyte size is increased, but platelet count is moderately reduced and thus the megakaryocyte-platelet picture resembles that of severe iron deficiency anemia. A more in depth examination of this model should delineate the effects of iron deficiency and hypoxia on megakaryocytopoiesis. The grey collie dog has cyclic hematopoiesis with large asynchronous fluctuations in all blood cell counts at approximately 2-week intervals. Megakaryocytes have not been studied. This model should be a tool to define the relationships between hematopoietic growth factors and differentiation of the various hematopoietic cell lineages. The br/br rabbit has a transient disturbance in fetal megakaryocytopoiesis and brachydactyly due to spontaneous amputation. Further study of this model may provide a better understanding of fetal megakaryocyte development and establish whether an association exists between the abnormal megakaryocytes and the limb amputations. The nude mouse with its severe T-lymphocyte deficiency has been studied to ascertain whether T cells play a regulatory role in normal and acute thrombocytopenia-stimulated megakaryocytopoiesis. The question of whether T cells or their products are responsible for reactive thrombocytosis in chronic inflammation could be examined with this model. These animal mutants have provided and should continue to provide important models for understanding the regulation of megakaryocytopoiesis and platelet production.
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Thrombopoiesis
Mean platelet volume
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Background: Megakaryocyte morphology plays an important role in thrombopoiesis. A defect in any stage of megakaryocytopoiesis can lead to dysmegakaryocytopoiesis and thrombocytopenia. This study was conducted to understand megakaryocytic alterations and their contribution in the diagnosis of cases of thrombocytopenia.Materials and Methods: This was a cross-sectional study was conducted on all consecutive cases of bone marrow aspirates of thrombocytopenia over a duration of one year in BPKIHS. Megakaryocyte morphology was studied with a 100X objective. Data were entered into Microsoft excel 10 and analysed with SPSS version 11.5. Descriptive statistics charted and Chi-square tests were done for inferential statistics to find any association at 95% Confidence Interval.Results: Among the 38 subjects, megakaryocytic thrombocytopenia (44.7%) was the most common cause of thrombocytopenia. Hypolobated megakaryocytes (63.2%), bare megakaryocytic nuclei (57.9%) were the common morphological changes in megakaryocytes. Odds of increased megakaryocyte count in megakaryocytic thrombocytopenia was found to be 12.5 times than for other causes of thrombocytopenia and the presence of bare megakaryocytic nuclei in MTP was statistically significant. (p –value<0.05)Conclusion: Many similarities were observed in megakaryocytic morphology among different hematological diseases. However, increased megakaryocyte count and presence of bare megakaryocytic nuclei, hypolobated forms were significant in megakaryocytic thrombocytopenia.
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Megakaryocytopoiesis
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Thrombopoiesis
Factor (programming language)
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A working hypothesis for the regulation of megakaryocytopoiesis is described on the basis of current data. The hypothesis proposes that in vivo megakaryocytes are generated by 1) the expansion of clonable progenitor cells into immature megakaryocytes by locally produced (and regulated) interleukin-3 (IL-3) and 2) the development and maturation of immature megakaryocytes by a dual system; by a lineage specific mechanism involving thrombopoietic stimuli in the steady state and thrombocytopenic conditions, and by a lineage nonspecific mechanism via IL-3 in damaged or reconstituting marrow. The hypothesis predicts that if IL-3 is a significant in vivo regulator of megakaryocyte formation and development, receptor for IL-3 should be present on megakaryocytes and may be vestigially on platelets. Small but significant levels of 125I IL-3 were found to bind to platelets from normal mice. The level of binding on platelets was found to be enhanced sevenfold from mice that had received high levels of irradiation followed by bone marrow transplantation. This contrasted with a twofold increase in the level of binding to platelets from mice made acutely thrombocytopenic with antiplatelet serum. The data suggest that IL-3 may be involved in the in vivo regulation of murine megakaryocytopoiesis and may be a significant factor in rebound thrombopoiesis following bone marrow damage.
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