Human thrombopoiesis depends on PKCdelta/PKCepsilon functional couple

A deeper 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 PKCepsilon 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 PKCepsilon and PKCdelta, which show functional and phenotypical reciprocity, at the same time to boost platelet production in vitro. Results show that PKCdelta, at the opposite of PKCepsilon, is persistently expressed during megakaryocytic differentiation, and a forced PKCdelta down-modulation impairs megakaryocyte maturation and platelet production. PKCdelta and PKCepsilon 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 PKCdelta/PKCepsilon ratio both in primary myelofibrosis and essential thrombocytemia, featured by impaired megakaryocyte differentiation and increased platelet production, respectively. Finally, we demonstrate that concurrent molecular targeting of both PKCdelta and PKCepsilon represents a strategy for in vitro platelet factories.