title: Human thrombopoiesis depends on Protein kinase Cδ/protein kinase Cε functional couple.
abstract: 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 PKCε 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 PKCε and PKCδ, which show functional and phenotypical reciprocity, at the same time as boosting platelet production in vitro. Results show that PKCδ, contrary to PKCε, is persistently expressed during megakaryocytic differentiation, and a forced PKCδ down-modulation impairs megakaryocyte maturation and platelet production. PKCδ and PKCε 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 PKCδ/PKCε 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 PKCδ and PKCε represents a strategy for in vitro platelet factories.
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Carubbi
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Masselli
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martini
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Italy.
authors.forename: Prisco
authors.initials: P
authors.lastname: Mirandola
authors.affiliation: Hematology Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Gobbi
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences (SBiBiT), University of Parma, Italy marco.vitale@unipr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Vitale
mesh_terms: D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000097:blood / Q000175:diagnosis / Q000378:metabolism; D011485:Protein Binding; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D013920:Thrombocythemia, Essential / Q000097:blood / Q000175:diagnosis / Q000378:metabolism; D034061:Thrombopoiesis / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon