Human thrombopoiesis depends on Protein kinase Cδ/protein kinase Cε functional couple
Human thrombopoiesis depends on Protein kinase Cδ/protein kinase Cε functional couple
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DOI：
10.3324/haematol.2015.137984
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发表时间：
2016-07-01
期刊：
影响因子：
10.1
通讯作者：
Vitale, Marco
中科院分区：
文献类型：
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作者：
Carubbi, Cecilia;Masselli, Elena;Vitale, Marco
更深入地了解驱动巨核细胞生成和血小板生成的分子事件对于调节临床应用的体外和体内血小板生成至关重要。我们以前记录了PKC β在人类和小鼠巨核细胞成熟和血小板释放的调节中的关键作用。然而，由于一些数据表明，不同的PKC亚型实现互补功能，我们靶向PKC β和PKC δ，这显示出功能和表型的相互作用，同时在体外促进血小板生成。结果表明，PKC δ，相反，PKC β，持续表达在巨核细胞分化，和强制PKC δ下调损害巨核细胞成熟和血小板的生产。PKC δ和PKC β在血小板生成中起着相反的作用，它们的平衡调节强烈影响血小板的生成。事实上，我们发现在原发性骨髓纤维化和原发性血小板增多症中，PKC δ/PKC β比值失衡，其特征分别是巨核细胞分化受损和血小板生成增加。最后，我们证明，同时分子靶向PKC δ和PKC β代表了体外血小板工厂的策略。
Adeeper understanding of the molecular events driving megakaryocytopoiesis and thrombopoiesis is essential to regulate in vitro and in vivo platelet production for clinical applications. We previously documented the crucial role of PKC epsilon in the regulation of human and mouse megakaryocyte maturation and platelet release. However, since several data show that different PKC isoforms fulfill complementary functions, we targeted PKC epsilon and PKC delta, which show functional and phenotypical reciprocity, at the same time as boosting platelet production in vitro. Results show that PKC delta, contrary to PKC epsilon, is persistently expressed during megakaryocytic differentiation, and a forced PKC delta down-modulation impairs megakaryocyte maturation and platelet production. PKC delta and PKC epsilon work as a functional couple with opposite roles on thrombopoiesis, and the modulation of their balance strongly impacts platelet production. Indeed, we show an imbalance of PKC delta/PKC epsilon ratio both in primary myelofibrosis and essential thrombocythemia, featured by impaired megakaryocyte differentiation and increased platelet production, respectively. Finally, we demonstrate that concurrent molecular targeting of both PKC delta and PKC epsilon represents a strategy for in vitro platelet factories.