Regulation of megakaryocyte maturation and platelet formation

Abstract

Summary. Each day in every human, approximately 1 · 10 11 platelets are produced by the cytoplasmic fragmentation of megakaryocytes (MK), their marrow precursor cells. Platelets are the predominating factor in the process of hemostasis and thrombosis. Recent studies have shown that platelets also play a hitherto unsuspected role in several other processes such as inflammation, innate immunity, neoangiogenesis and tumor metastasis. The late phases of MK differentiation identified by polyploidization, maturation and organized fragmentation of the cytoplasm leading to the release of platelets in the blood stream represent a unique model of differentiation. The molecular and cellular mechanisms regulating platelet biogenesis are better understood and may explain several platelet disorders. This review focuses on MK polyploidization, and platelet formation, and discusses their alteration in some platelet disorders.

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

“…1D-F). A distinctive feature of megakaryopoiesis is endomitosis, DNA replication in the absence of cell division that results from an incomplete M phase due to a failure in late cytokinesis (Bluteau et al 2009). The rapid transcriptional repression of genes involved in mitotic nuclear division and microtubule organization (Fig.…”

Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function

“…The cause of the block in ploidy in Shp1-deficient megakaryocytes remains undefined but suggests a defect in the formation of the cleavage furrow and/or cytokinesis at the 2N/4N transition during the endomitotic process. 49 Myosin IIA and the small GTPase RhoA are critical regulators of contractile ring assembly and cytokinesis that might be regulated by Shp1. 49 Intriguingly, differences in integrin-mediated functions exhibited by Shp1-and Shp2-deficient megakaryocytes and platelets suggest that Shp1 and Shp2 have different functions in the 2 cell types.…”

“…49 Myosin IIA and the small GTPase RhoA are critical regulators of contractile ring assembly and cytokinesis that might be regulated by Shp1. 49 Intriguingly, differences in integrin-mediated functions exhibited by Shp1-and Shp2-deficient megakaryocytes and platelets suggest that Shp1 and Shp2 have different functions in the 2 cell types. For example, Shp1-deficient megakaryocytes spread normally on fibrinogen-coated surfaces, whereas Shp1-deficient platelets did not spread to the same extent as control platelets on the same surface.…”

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

“…The thrombopoietin receptor (TPO-R) pathway is essential for maintenance of HSCs compartment and regulates the entire process of platelet biogenesis until platelet release. Mk maturation is characterized by cell polyploidization through endomitosis, a modification of the cell cycle leading to formation of large polylobulated nuclei having up to 256 times the normal chromosome content [12]. Mk maturation also implies intense protein synthesis and considerable increase in cytoplasmic mass with development of platelet-specific structures (such as organelles, granules, membrane integrins, cytoskeletal proteins) and of multiple surface-connected membrane invaginations (demarcation membrane system, DMS) that are regarded as a membrane reservoir for proplatelet extension.…”

“…First, I will include a brief overview of the process of platelet biogenesis, which exclusively aims to introduce some physiological mechanisms that are relevant to discussion of pathogenesis. I refer to several recent reviews for detailed treatment of this topic [11][12][13][14].…”