Human thrombopoiesis depends on Protein kinase Cδ/protein kinase Cε functional couple

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.