Delivering new insight into the biology of megakaryopoiesis and thrombopoiesis

Battinelli, Elisabeth M.; Hartwig, John H.; Italiano, Joseph E.

doi:10.1097/moh.0b013e3282bad151

Cited by 73 publications

(60 citation statements)

References 57 publications

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“…A hallmark of mature megakaryocytes is their capacity to reach high ploidy levels through endomitosis. 38 An analysis of bone marrow showed a normal ploidy distribution in GPIbβ -/-megakaryocytes. This was somewhat unexpected since an increased proportion of high ploidy megakaryocytes has been reported in a Bernard-Soulier patient 6 and in mice expressing a GPIbα transgene deleted in its cytoplasmic domain, 20 the latter effect being observed only under stress thrombopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Strassel¹,

Eckly²,

Léon³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundGiant platelets and thrombocytopenia are invariable defects in the Bernard-Soulier syndrome caused by deficiency of the GPIb-V-IX complex, a receptor for von Willebrand factor supporting platelet adhesion to the damaged arterial wall. Various properties of this receptor may be considered potential determinants of the macrothrombocytopenia. Design and MethodsTo explore the underlying mechanisms of the disease, megakaryopoiesis was studied in a mouse model deficient in GPIbβ. Megakaryocytes were initially characterized in situ in the bone marrow of adult mice, after which their capacity to differentiate into proplateletbearing cells was evaluated in cultured fetal liver cells. ResultsThe number of megakaryocyte progenitors, their differentiation and progressive maturation into distinct classes and their level of endoreplication were normal in GPIbβ -/-bone marrow. However, the more mature cells exhibited ultrastructural anomalies with a thicker peripheral zone and a less well developed demarcation membrane system. GPIbβ -/-megakaryocytes could be differentiated in culture from Lin -fetal liver cells in normal amounts but the proportion of cells able to extend proplatelets was decreased by 41%. Moreover, the GPIbβ -/-cells extending proplatelets displayed an abnormal morphology characterized by fewer pseudopodial extensions with thicker shaft sections and an increased diameter of the terminal coiled elements. GPIbβ -/-released platelets were larger but retained a typical discoid shape. Proplatelet formation was similarly affected in bone marrow explants from adult mice examined by videomicroscopy. The marginal microtubular ring contained twice as many tubulin fibers in GPIbβ -/-proplatelet buds in cultured and circulating platelets. ConclusionsAltogether, these findings point to a role of the GPIb-V-IX complex intrinsic to megakaryocytes at the stage of proplatelet formation and suggest a functional link with the underlying microtubular cytoskeleton in platelet biogenesis.Key words: megakaryocyte, platelet, Bernar-Soulier, microtubules, GPIb-V-IX.Citation: Strassel C, Eckly A, Léon C, Petitjean C, Freund M, Cazenave J-P, Gachet C, and Lanza F. Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome. Haematologica 2009; 94:800-810. doi:10.3324/haematol.2008 This is an open-access paper.

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Section: Discussionmentioning

confidence: 99%

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Strassel¹,

Eckly²,

Léon³

et al. 2009

Haematologica

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“…Lastly, mature MKs develop long cytoplasmic extensions, known as proplatelets, that release large numbers of platelets into the circulation. 2 The processes of polyploidization and proplatelet formation are unique to the MK lineage. Both processes are characterized by dramatic changes in the organization of the microtubule (MT) cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production

Iancu‐Rubin

Gajzer

Tripodi

et al. 2011

Blood

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The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MTregulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relationship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which downregulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis. (Blood. 2011; 117(17):4580-4589) IntroductionMegakaryocytopoiesis is a complex process in which hematopoietic stem cells proliferate, differentiate, undergo terminal maturation, and give rise to circulating platelets. 1 During the early stages of megakaryocytopoiesis, megakaryocyte (MK) progenitors are diploid, proliferative and express early markers of the MK lineage. In the later stages, MKs cease to divide but continue to replicate their DNA and become polyploid (ie, DNA content Ͼ 2N). This is accompanied by expression of more MK-specific markers and an increase in nuclear complexity and cell size. Lastly, mature MKs develop long cytoplasmic extensions, known as proplatelets, that release large numbers of platelets into the circulation. 2 The processes of polyploidization and proplatelet formation are unique to the MK lineage. Both processes are characterized by dramatic changes in the organization of the microtubule (MT) cytoskeleton. After multiple rounds of normal cell divisions, MK progenitors switch from a normal to a form of abortive mitosis, known as endomitosis, in which MKs enter and progress normally through mitosis but fail to undergo cytokinesis and divide. [3][4][5] This process is mediated by an atypical organization of MTs that forms a complex, spherical mitotic spindle. 4,6 Recent studies have suggested that the failure of MKs to complete cytokinesis is associated, in part, with defective elongation of spindle MTs. 5 On the other hand, studies by Patel et al have demonstrated that the cytoplasm of mature MKs contains bundles of polymerized MTs that extend into the proplatelets and provide their structural scaffold ...

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“…Diğer taraftan, HKH transplantasyonu veya yüksek doz kemoterapi sonrası oluşan şiddetli trombositopeni hastalar için çok ciddi sorun oluşturmaktadır. Trombositopeninin tedavisi konusunda iki farklı yaklaşım ileri sürülmüştür [21]. Birincisi; trombosit üretimini arttırmak için megakaryopoezin endojen olarak çeşitli ajanlarla uyarımıdır.…”

Section: Discussionunclassified

Differentiation of hematopoietic stem cells isolated from peripheral blood to megakaryocyte

Özakpınar¹,

Maurer²,

Adiguzel³

et al. 2013

Turk J Bioch

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Delivering new insight into the biology of megakaryopoiesis and thrombopoiesis

Cited by 73 publications

References 57 publications

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production

Differentiation of hematopoietic stem cells isolated from peripheral blood to megakaryocyte

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