UMR 1170, Institut National de la Santé et de la Recherche Médicale, Univ. Paris-Sud, Université Paris-Saclay, Gustave Roussy Cancer Campus, Equipe Labellisée Ligue Nationale Contre le Cancer , Villejuif, France.
Platelets. 2020 Aug 17;31(6):707-716. doi: 10.1080/09537104.2019.1667497. Epub 2019 Sep 22.
Mammal megakaryocytes (MK) undergo polyploidization during their differentiation. This process leads to a marked increase in the MK size and of their cytoplasm. Contrary to division by classical mitosis, ploidization allows an economical manner to produce platelets as they arise from the fragmentation of the MK cytoplasm. The platelet production correlates to the entire MK cytoplasm mass that depends both upon the number of MKs and their size. Polyploidization occurs by several rounds of DNA replication with at the end of each round an aborted mitosis at late phase of cytokinesis. As there is also a defect in karyokinesis, MKs are giant cells with a single polylobulated nucleus with a 2N ploidy. However, polyploidization does not increase platelet production because it requires a parallel development of MK organelles such as mitochondria, granules and the demarcation membrane system. MK polyploidization is regulated by extrinsic factors, more particularly by thrombopoietin (TPO), which during a platelet stress increases first polyploidization before enhancing the MK number and by transcription factors such as RUNX1, GATA1, and FLI1 that regulate MK differentiation explaining why polyploidization and cytoplasmic maturation are intermingled. MK polyploidization is ontogenically regulated and is markedly altered in malignant myeloid disorders such as acute megakaryoblastic leukemia and myeloproliferative disorders as well as in hereditary thrombocytopenia, more particularly those involving transcription factors or signaling pathways. In addition, MKs arising from progenitors have a much lower ploidy than leading to a low yield of platelet production . Thus, it is tempting to find approaches to increase MK polyploidization . However, these approaches require molecules that are able to simultaneously increase MK polyploidization and to induce terminal differentiation. Here, we will focus on the regulation by extrinsic and intrinsic factors of MK polyploidization during development and pathological conditions.
哺乳动物巨核细胞（MK）在分化过程中经历多倍体化。这个过程导致 MK 大小及其细胞质的显著增加。与经典有丝分裂的分裂不同，多倍体化允许以经济的方式产生血小板，因为它们是从 MK 细胞质的碎片化中产生的。血小板的产生与整个 MK 细胞质质量相关，这取决于 MK 的数量及其大小。多倍体化通过几轮 DNA 复制发生，在每个复制周期结束时，在胞质分裂的晚期发生有丝分裂中止。由于核分裂也存在缺陷，MK 是具有单个多核化核的巨大细胞，具有 2N 倍体。然而，多倍体化不会增加血小板的产生，因为它需要 MK 细胞器如线粒体、颗粒和界膜系统的平行发育。MK 多倍体化受外在因素的调节，更特别是受血小板生成素（TPO）的调节，在血小板应激期间，TPO 首先增加多倍体化，然后增强 MK 数量，并通过转录因子如 RUNX1、GATA1 和 FLI1 调节 MK 分化，解释了为什么多倍体化和细胞质成熟是交织在一起的。MK 多倍体化是在胚胎发生过程中受到调节的，在恶性髓系疾病如急性巨核细胞白血病和骨髓增生性疾病以及遗传性血小板减少症中显著改变，特别是那些涉及转录因子或信号通路的疾病。此外，来自祖细胞的 MK 具有低得多的多倍体，导致血小板产生的产量低。因此，人们试图找到增加 MK 多倍体化的方法。然而，这些方法需要能够同时增加 MK 多倍体化并诱导终末分化的分子。在这里，我们将重点讨论在发育和病理条件下，外在和内在因素对 MK 多倍体化的调节。
