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Centromere movement during polyploidizing megakaryocytes. TPO-treated primary megakaryocytes were stained with anticentromere antibody (red, first column), anti–α-tubulin antibody (green, second column), DAPI (blue, third column), and triple staining (fourth column) during mitosis. (A) Megakaryocyte in interphase. (B) Megakaryocytes in prometaphase. (C) Megakaryocyte with ploidy 8N at the stage just before metaphase. (D) Megakaryocyte with ploidy 8N in metaphase. (E) Megakaryocyte with ploidy 8N in anaphase A. (F) Megakaryocyte with ploidy 16N in anaphase A.
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Megakaryocytes undergo a unique differentiation program, becoming polyploid through repeated cycles of DNA synthesis without concomitant cell division. However, the mechanism underlying this polyploidization remains totally unknown. It has been postulated that polyploidization is due to a skipping of mitosis after each round of DNA replication. We...
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... Mitotic spindle poles of endomitotic megakaryocytes are usually multipolar owing to supernumerary centrioles (figure 2) [79]. The mitotic spindle self-assembles and mitotic regulatory proteins, such as the error correction kinase Aurora B and the microtubule anti-parallel cross-linker protein regulating cytokinesis 1, were expressed in cultured megakaryocytes, which subsequently were found to enter telophase [80]. ...
... Asymmetric chromosome segregation was mediated by multipolar spindles, indicating that anaphase A occurred. However, the spindle poles did not move apart, suggesting that megakaryocytes did not enter anaphase B. Early studies demonstrated that endomitosis was arrested during anaphase B, causing megakaryocytes to skip telophase and cytokinesis [78,79]. ...
Platelets are blood cells derived from megakaryocytes that play a central role in regulating haemostasis and vascular integrity. The microtubule cytoskeleton of megakaryocytes undergoes a critical dynamic reorganization during cycles of endomitosis and platelet biogenesis. Quiescent platelets have a discoid shape maintained by a marginal band composed of microtubule bundles, which undergoes remarkable remodelling during platelet activation, driving shape change and platelet function. Disrupting or enhancing this process can cause platelet dysfunction such as bleeding disorders or thrombosis. However, little is known about the molecular mechanisms underlying the reorganization of the cytoskeleton in the platelet lineage. Recent studies indicate that the emergence of a unique platelet tubulin code and specific pathogenic tubulin mutations cause platelet defects and bleeding disorders. Frequently, these mutations exhibit dominant negative effects, offering valuable insights into both platelet disease mechanisms and the functioning of tubulins. This review will highlight our current understanding of the role of the microtubule cytoskeleton in the life and death of platelets, along with its relevance to platelet disorders.
... An alternative mechanism to maximize transcription in polyploid cells could be to increase the nuclear surface-to-volume ratio by changing the shape of polyploid nuclei. Indeed, some polyploid nuclei, such as those of silk glands, megakaryocytes, trophoblast giant cells and tomato fruit cells, have highly lobulated nuclei (Bourdon et al., 2012;Buntrock et al., 2012;Henderson and Locke, 1991;Klisch et al., 2005;Nagata et al., 1997). Whether and how changes in nuclear shape influence transcription in polyploid cells remains to be determined. ...
Polyploid cells contain multiple genome copies and arise in many animal tissues as a regulated part of development. However, polyploid cells can also arise due to cell division failure, DNA damage or tissue damage. Although polyploidization is crucial for the integrity and function of many tissues, the cellular and tissue-wide consequences of polyploidy can be very diverse. Nonetheless, many polyploid cell types and tissues share a remarkable similarity in function, providing important information about the possible contribution of polyploidy to cell and tissue function. Here, we review studies on polyploid cells in development, underlining parallel functions between different polyploid cell types, as well as differences between developmentally-programmed and stress-induced polyploidy.
... Hence, cytokinesis includes cytoplasmic division finally giving rise to two daughter cells, even when some exceptions have been described in the early embryonic stages of the fruit fly model Drosophila (Schejter and Wieschaus, 1993;Kiseleva et al., 2001). In mammals, megakaryocytes (blood platelets), hepatocytes, and heart muscle cells perform nuclear division without cytokinesis, leading to a high proportion of multi-nucleated cells (Nagata et al., 1997;Ahuja et al., 2007;Alberts et al., 2007;Margall-Ducos et al., 2007;Lordier et al., 2008). However, the endothelium of vessels in vivo physiologically does not include binucleated phenotypes, therefore evidencing that our findings are directly correlated with T. gondii infections. ...
Toxoplasma gondii is an obligate intracellular parasite that modulates a broad range of host cell functions to guarantee its intracellular development and replication. T. gondii includes three classical clonal lineages exhibiting different degrees of virulence. Regarding the genetic diversity of T. gondii circulating in Europe, type II strains and, to a lesser extent, type III strains are the dominant populations, both in humans and animals. Infections with the type I strain led to widespread parasite dissemination and death in mice, while type III is considered avirulent. Previously, we demonstrated that primary endothelial cells infected with the T. gondii RH strain (haplotype I) were arrested in the G2/M-phase transition, triggering cytokinesis failure and chromosome missegregation. Since T. gondii haplotypes differ in their virulence, we here studied whether T. gondii-driven host cell cycle perturbation is strain-dependent. Primary endothelial cells were infected with T. gondii Me49 (type II strain) or NED (type III strain), and their growth kinetics were compared up to cell lysis (6-30 h p. i.). In this study, only slight differences in the onset of full proliferation were observed, and developmental data in principle matched those of the RH strain. FACS-based DNA quantification to estimate cell proportions experiencing different cell cycle phases (G0/1-, Sand nd G2/M-phase) revealed that Me49 and NED strains both arrested the host cell cycle in the S-phase. Cyclins A2 and B1 as key molecules of Sand M-phase were not changed by Me49 infection, while NED infection induced cyclin B1 upregulation. To analyze parasite-driven alterations during mitosis, we demonstrated that both Me49 and NED infections led to impaired host cellular chromosome segregation and irregular centriole overduplication. Moreover, in line with the RH strain, both strains boosted the proportion of binucleated cells within infected endothelial cell layers, thereby indicating enhanced cytokinesis failure. Taken together, we demonstrate that all parasite-driven host cell cycle arrest, chromosome missegregation, and binucleated phenotypes are T. gondii-specific but strain independent.
... The evidence that polyploidization is an intrinsic component of megakaryocyte differentiation indicates that these two events are regulated by a coordinated and specific gene regulatory programme (Mazzi et al., 2018). Part of this programme must involve one or more alterations in the expression of mitotic factor(s) that result in polyploidization, because studies have indicated that megakaryocyte polyploidization is caused by abortive mitoses known as endomitoses (Nagata et al., 1997;Vitrat et al., 1998). The exact nature of the mitotic defect(s) and their underlying molecular mechanism(s) are still unclear. ...
Platelets are found only in mammals. Uniquely, they have a log Gaussian volume distribution and are produced from megakaryocytes, large cells that have polyploid nuclei. In this Hypothesis, we propose that a possible explanation for the origin of megakaryocytes and platelets is that, ∼220 million years ago, an inheritable change occurred in a mammalian ancestor that caused the haemostatic cell line of the animal to become polyploid. This inheritable change occurred specifically in the genetic programme of the cell lineage from which the haemostatic cell originated and led, because of increase in cell size, to its fragmentation into cytoplasmic particles (platelets) in the pulmonary circulatory system, as found in modern mammals. We hypothesize that these fragments originating from the new large haemostatic polyploid cells proved to be more efficient at stopping bleeding, and, therefore, the progeny of this ancestor prospered through natural selection. We also propose experimental strategies that could provide evidence to support this hypothesis.
... Possibly, these fail to implant or simply a selective process favors the 2n cells and therefore M rare in pregnancies and infants. Thus, 2n/4n M in living patients has been reported in at least 29 cases since 1967 [59] Endopolyploidy is presented as P of some normal tissues in 2n body, e.g., in myocard [53], liver [8,18], placenta [71,79], bone marrow [51,75]. ...
Theoretical background. Regarding aberrations (numerical or structural changes) of the chromosomes (chrs) on this and next lesson, let us learn first their general structure. The chr have a centromere (с), short arm (p arm) and long arm (q arm). The c contains the kinetochore for correct spindle attachment and sister chromatids segregation to opposite poles during cell division. Sister chromatids remain joined by cohesin at the para-centric heterochromatin until anaphase, when cohesin removal makes them free. This protein facilitates DNA replication, repair and transcription, regulates chrs condensation, pairing and the orientation of sister kinetochores in meiosis I, non-homologous cs coupling, chr structure, etc. [47]. The pictures of the chrs showing their relative size, homologous groups and landmarks are called idiograms. By convention, the p-arm is always at the top of them. The arms are nearly of the same length in metacentric chr; the chr is said sub-metacentric, if one arm is shorter a little; when it is very short, the chr is said acrocentric, when it is almost invisible, the chr is telocentric (Fig.1). For example, in human karyotype, chr pairs 13, 14, 15, 21, 22 are acrocentric [52]. The p-arms of these carry nucleolar organising regions (NORs), containing genes coding for rRNA [33]. The Y chr is also acrocentric [52]. Arms terminus, the telomere (ptel, qtel), is a highly conserved repetitive sequence that prevents end-end chr fusion, and is important for attachments of chr ends to the nuclear envelope, particularly, in meiosis. The telomere shortening is associated with cell ageing. The notation 3ptel means the telomere of the short arm of chr 3. Several staining methods cause the chrs to take on a banded appearance. Patterns of the bands are specific for each chr, allowing gene mapping and structural changes recording. The number of bands depends on chr contraction, i.e., prophase chrs have more bands than metaphase ones [33]. The Cytogenetic Banding Nomenclature for positional mapping was standardised to allow cytogenetic information flow and storage. Numbering starts from the c and continues to the end of each arm. The arms are divided into a number of regions by "land-mark" bands, detected in microscopy. They are numbered sequentially within each region. The cytogenetic bands are labeled p1, p2, p3, q1, q2, q3, etc. At higher microscopic resolutions, sub-bands and sub-sub-bands can be seen (Fig.2) and numbered from the c out toward the telomere. E. g., the cytogenetic map location of the CFTR gene is 7q31.2, which indicates it is on chr 7, q arm, band 3, sub-band 1, and sub-sub-band 2 [28]. Fig.1. Classification of chromosomes based on short arm length. By D.B. Pylypiv.
... Il se définit par une anomalie de la mitose des cellules provoquant ainsi l'accroissement de la taille des mégacaryocytes jusqu'à la maturation finale (65,66). Des études montrent que l'accomplissement des étapes finales de la mitose est suspendu vu que l'anaphase B, la télophase et la cytocinèse sont absentes dans l'endomitose, ensuite les cellules redémarrent la division suivante en entrant dans la phase G1 de la mitose pour assurer la réplication de l'ADN (67,68). (77). ...
Les stratégies actuelles pour éradiquer les cellules cancéreuses consistent à induire l’apoptose ou la différenciation. Plusieurs substances naturelles sont utilisées pour réamorcer la différenciation bloquée durant la transformation cancéreuse des cellules. En 2006, Leger et al, ont montré l’implication de l’apoptose durant la différenciation mégacaryocytaire des HELs (lignée erythroleucémique humaine) par 10μM de diosgénine. Des études récentes parlent de l’importance de l’autophagie durant la différenciation mégacaryocytaire. Notre travail vise à montrer l’implication d’une autre voie de mort cellulaire nommée « autophagie » dans ce processus. Nos résultats ont montré la stimulation du flux autophagique après le traitement des HELs par 10 μM de diosgénine. Cette stimulation s’est manifestée par la surexpression de l’Atg7 et l’accumulation de la forme LC3A/B-II au fur et à mesure de la progression de la différenciation. Dans le but d’interroger le rôle de l’autophagie, on a modulé cette voie 2h avant ou après (jours 2 et 4) de l’induction de la différenciation par la diosgénine On a montré que l’inhibition de l’autophagie par la 3-methyladénine (3-MA ; 2 mM) réprime la polyploïdie au jours 4 et 8 de la différenciation tandis que l’activation de l’autophagie par metformine (Met ; 0.25 mM) n’induit aucun effet quel que soit le temps de traitement. En outre, on a montré que la modulation de l’autophagie affecte la maturation membranaire (expression génomique de glycoprotéine V) des HELs différenciées par la diosgénine. L’inhibition de l’autophagie avant et après l’induction de la différenciation par la diosgénine réprime fortement l’expression de GpV aux jours 4 et 8. Tandis que l’activation de l’autophagie par la metformine, active l’expression de GpV à la fin de la différenciation indépendamment du temps de traitement. En parallèle, on a montré que la modulation de l’autophagie durant la différenciation mégacaryocytaire induite par la diosgénine (10 μM) n’affecte par la fragmentation d’ADN. En résumé, la voie autophagique est impliquée durant la différenciation mégacaryocytaire des HELs induite par la diosgénine(10 μM). Pour déceler plus précisément le rôle de l’autophagie dans ce processus et son interaction avec la voie apoptotique, plus d’investigation devraient être menés.
... After assembling multipolar spindles, MKs skip late anaphase and cytokinesis, generating cells that contain a single multilobate polyploid nucleus. Endomitosis is initiated by the secreted signal thrombopoietin (Nagata et al., 1997a;b) and after up to 6 rounds of polyploidization, the DNA content of MK nuclei reaches up to 128C (Winkelmann et al., 1987;Ravid et al., 2002). ...
Most animal cells are diploid, containing two copies of each chromosome. Establishment of proper bipolar mitotic spindle containing two centrosomes, one at each pole contributes to accurate chromosome segregation. This is essential for the maintenance of genome stability, tissue and organism homeostasis. However, numerical deviations to the diploid set are observed in healthy tissues. Polyploidy is the doubling of the whole chromosome set and aneuploidy concerns the gain or loss of whole chromosomes. Importantly, whole genome duplications and aneuploidy have also been associated to pathological conditions. For example, variations to genome content are associated with chromosome instability and cancer development, however their exact contribution to cancer genome remains poorly understood.In the first part of my PhD project, I investigated the consequences of polyploidy during cell division. I found that the presence of extra DNA and extra centrosomes generated invariably multipolar spindles. Then I identified contributors to the multipolar status using in vivo approaches in Drosophila neural stem cells and in vitro culture of cancer cells. Further I combined DNA and spindle perturbations with computer modelling and found that in polyploid cells, the presence of excessive DNA acts as a physical barrier blocking spindle pole coalescence and bipolarity. Indeed, laser ablation to disrupt and increase in microtubule stability and length to bypass the DNA-barrier could rescue bipolar spindle formation. This discovery challenges the current view that suggested extra-centrosomes as only contributor to spindle multipolarity and provides a rational to understand chromosome instability typical of polyploid cells.The aim of the second part of my PhD project was to generate a novel tool to quantitively probe chromosome loss in vivo in Drosophila tissues. Aneuploidy has been observed in various physiological tissues, however the frequency of this error remained highly debatable. In addition, tools developed so far to assess aneuploidy lack a temporal dimension. To circumvent this, I used the expression of a GFP report gene driven by the GAL4/UAS system and its inhibition by GAL80. In principle, the random loss of the chromosome carrying the GAL80 sequence leads to GFP appearance in aneuploid cells that can therefore be followed in live tissues. I found that chromosome loss was extremely infrequent in most tissues of the wild type fly. This tool combined with fluorescent marker and/or tested in various genetic background, might help understanding mechanisms behind aneuploidy genesis and outcome in vivo.While developing this tool, I discovered that in the larval brain, GFP cells where not a by-product of chromosome loss but rather an unexpected mis-regulation in the expression of the GAL80 gene. These results have strong implications for the Drosophila community as it can result in false positive in clonal experiments. Further, I discovered a mosaicism and plasticity of the Drosophila brain in neural stem cells for gene expression which differs from other organs and that is influenced by environmental stimuli. This possibly reflects a certain level of plasticity in the brain necessary for neuronal diversity, adaptation and survival.
... The ANKRD26 locus has been in fact associated to autosomal dominant thrombocytopenia, a bleeding disorder caused by platelet depletion (Noris et al, 2011). The megakaryocyte, the platelet cellular precursor, physiologically reaches a hyperploid state via consecutive rounds of endomitosis, thereby physiologically carrying supernumerary centrosomes (Nagata et al, 1997). Thus, megakaryocytes must naturally prevent PIDDosome activation. ...
Centrosome amplification results into genetic instability and predisposes cells to neoplastic transformation. Supernumerary centrosomes trigger p53 stabilization dependent on the PIDDo-some (a multiprotein complex composed by PIDD1, RAIDD and Caspase-2), whose activation results in cleavage of p53's key inhi-bitor, MDM2. Here, we demonstrate that PIDD1 is recruited to mature centrosomes by the centriolar distal appendage protein ANKRD26. PIDDosome-dependent Caspase-2 activation requires not only PIDD1 centrosomal localization, but also its autoproteoly-sis. Following cytokinesis failure, supernumerary centrosomes form clusters, which appear to be necessary for PIDDosome activation. In addition, in the context of DNA damage, activation of the complex results from a p53-dependent elevation of PIDD1 levels independently of centrosome amplification. We propose that PIDDosome activation can in both cases be promoted by an ANKRD26-dependent local increase in PIDD1 concentration close to the centrosome. Collectively, these findings provide a paradigm for how centrosomes can contribute to cell fate determination by igniting a signalling cascade.
... Au cours de ce phénomène continu, stimulé par la TPO, les CFU-MK se différencient en mégacaryoblastes de stade I puis en mégacaryocytes basophiles ou de stade II pour finalement aboutir aux mégacaryocytes matures de stade III, également nommés mégacaryocytes plaquettogènes. Il existe tout au long de cette évolution une augmentation de la ploïdie par endoréplication (Nagata et al. 1997;Vitrat et al. 1998;Lordier et al. 2008) des MK jusqu'à 16 N en moyenne chez l'Homme et 128 N chez la souris (Tomer et al. 1988;Corash et al. 1989). Ceci s'accompagne d'une accélération de la Thon et al, 2010. ...
Les plaquettes sanguines circulent dans le sang au repos, cet état inactivé étant maintenu par la production de prostacycline et de monoxyde d'azote par l'endothélium vasculaire. Ces deux agents activent respectivement les voies des nucléotides cycliques : AMPc et GMPc. La prostacycline (ou prostaglandine I2), après liaison au récepteur IP, active l'adénylate cyclase (AC) via une protéine Gs. L'AC activée est responsable de la formation d'AMPc intraplaquettaire qui conduit à une inhibition de l'activation plaquettaire. Afin de permettre l'activation plaquettaire, le taux d'AMPc est réprimé i) par l'action des phosphodiestérases (PDE), qui le dégradent, ii) l'ADP, qui en se fixant sur P2Y12 active une Gi inhibitrice de l'AC, iii) par son efflux du cytosol via notamment la protéine d'efflux MRP4 (ABCC4), et iv) par une compartimentation subcellulaire de la voie de l'AMPc, mécanisme très peu documenté dans les plaquettes. Outre son rôle dans l'homéostasie de l'AMPc, de récentes études suggèrent que MRP4 serait également associée à des états de résistance plaquettaire à l'aspirine. En effet, un traitement par aspirine au long cours induirait une surexpression de MRP4 dans les plaquettes et cette surexpression serait par la suite responsable de l'efflux de l'aspirine hors des plaquettes, diminuant alors son efficacité. Les travaux présentés dans cette thèse ont eu pour objectif d'étudier la régulation de la voie de l'AMPc sous forme de microdomaines et l'impact d'un traitement par l'aspirine in vivo sur l'expression de MRP4 et sa répercussion sur l'homéostasie de l'AMPc. L'étude de la répartition des acteurs de la voie de l'AMPc révèlent une répartition non homogène au sein des membranes. En effet, une partie des acteurs sont présents hors des radeaux lipidiques membranaires bien qu'une fraction de PKA ainsi que de Gi soient présents dans les radeaux lipidiques. Cette répartition suggère diverses voies de régulation de la voie de l'AMPc. En effet, la présence d'acteurs hors des radeaux lipidiques est compatible avec le modèle d'organisation sous forme de microdomaines à AMPc comprenant la voie de synthèse (Gs, ACIII), l'effecteur PKA mais également la voie de régulation par les PDEs 2A et 3A. Ces microdomaines pourraient alors réguler localement la réponse plaquettaire. Par ailleurs, la présence d'acteurs de la voie de l'AMPc dans les radeaux lipidiques est compatible avec le modèle d'organisation ayant pour rôle de produire de l'AMPc qui diffuse plus facilement dans le cytoplasme (absence de PDE à proximité) pour exercer son effet inhibiteur, tout en maintenant un niveau d'inhibition contraint comme en témoigne l'augmentation de l'effet inhibiteur d'un activateur de la voie de l'AMPc lors de destruction des radeaux lipidiques. Ainsi l'organisation de la voie de l'AMPc sous différentes formes, en microdomaines AMPc ou non, pourrait impliquer des degrés différents d'inhibition plaquettaire par l'AMPc. Pour le second objectif, l'étude de différentes voies d'administration de l'aspirine chez deux souches de souris nous a permis de définir la voie orale comme étant la voie la plus appropriée pour l'étude de l'effet anti plaquettaire de l'aspirine. Son effet est mesurable 30 min après administration et reste mesurable à 3 heures avec une meilleure reproductibilité chez la souche C56/BL6. La dose de 100 mg/Kg induit une augmentation du temps de saignement et inhibe l'activité plaquettaire comme le montre une inhibition de 50 % de l'agrégation au collagène et la baisse de 85 % de la production de thromboxane B2. L'administration de l'aspirine durant 4 jours permet d'induire une augmentation de l'expression plaquettaire de MRP4 d'un facteur 2,5. Ce travail a permis de mieux caractériser le rôle de MRP4 dans la voie de l'AMPc et de définir le modèle préclinique d'administration de l'aspirine afin d'étudier le rôle de MRP4 dans la résistance au traitement.
... CTD, carboxyl-terminal domain; JMD, juxtamembrane domain; KID, kinase insert domain; NRP1/2, neuropilin 1/2; PlGF, placenta growth factor; sVEGFR1/2, soluble VEGFR1/2; TKD1, ATP binding domain; TKD2, phosphotransferase domain; TMD, transmembrane domain; Y, tyrosine. their ability to attain states of high ploidy (up to 256 N) by endomitosis, a process that involves multiple cycles of aborted late anaphase and cytokinesis and the re-entrance into the G1 phase of the higher polyploidy cell cycle (Nagata et al, 1997;Bluteau et al, 2009 (Kaushansky, 2008). Recently, it was shown that MKPs could be generated directly from a subset of CD41 + LSK (Lin À Sca-1 + c-Kit + ) cells bypassing megakaryocyte-erythrocyte progenitors (MEPs) in mice (Nishikii et al, 2015). ...
It is well known that vascular endothelial growth factors (VEGFs) and their receptors (vascular endothelial growth factor receptors, VEGFRs) are expressed in different tissues, and VEGF-VEGFR loops regulate a wide range of responses, including metabolic homeostasis, cell proliferation, migration and tubuleogenesis. As ligands, VEGFs act on three structurally related VEGFRs (VEGFR1, VEGFR2 and VEGFR3 [also termed FLT1, KDR and FLT4, respectively]) that deliver downstream signals. Haematopoietic stem cells (HSCs), megakaryocytic cell lines, cultured megakaryocytes (MKs), primary MKs and abnormal MKs express and secrete VEGFs. During the development from HSCs to MKs, VEGFR1, VEGFR2 and VEGFR3 are expressed at different developmental stages, respectively, and re-expressed, e.g., VEGFR2, and play different roles in commitment, differentiation, proliferation, survival and polyplodization of HSCs/MKs via autocrine, paracrine and/or even intracrine loops. Moreover, VEGFs and their receptors are abnormally expressed in MK-related diseases, including myeloproliferative neoplasms, myelodysplastic syndromes and acute megakaryocytic leukaemia (a rare subtype of acute myeloid leukaemia), and they lead to the disordered proliferation/differentiation of bone marrow cells and angiogenesis, indicating that they are closely related to these diseases. Thus, targeting VEGF-VEGFR loops may be of potential therapeutic value.
