PACAP and its receptor VPAC1 regulate megakaryocyte maturation: therapeutic implications.
Megakaryocytes and platelets express the Gs-coupled VPAC1 receptor, for which the pituitary adenylyl cyclase-activating peptide (PACAP) and the vasointestinal peptide (VIP) are agonists. We here demonstrate a regulatory role for VPAC1 signaling during megakaryopoiesis. A total of 2 patients with trisomy 18p with PACAP overexpression and transgenic mice overexpressing PACAP in megakaryocytes have thrombopathy, a mild thrombocytopenia, and a reduced number of mature megakaryocytes in their bone marrow. In vitro differentiation of hematopoietic stem cells from the patient and transgenic mice shows a reduced number of megakaryocyte colonies compared with controls. The addition of PACAP, VIP, or the adenylyl cyclase activator forskolin to CD34(+) cells inhibits megakaryocyte differentiation. In contrast, neutralizing monoclonal anti-PACAP (PP1A4) or anti-VPAC1 (23A11) antibodies inhibit cAMP formation and stimulate megakaryopoiesis in a thrombopoietin-independent manner. Moreover, wild-type mice obtain an increased platelet count after subcutaneous injection of PP1A4 or 23A11. These antibodies also elevate platelet numbers in animal models of myelosuppressive therapy and in GATA1-deficient mice with congenital thrombocytopenia. Furthermore, 23A11 stimulates the in vitro megakaryocyte differentiation of both normal and GATA1-deficient human CD34(+) cells. Together, our data strongly suggest that VPAC1 signaling tempers normal megakaryopoiesis, and that inhibition of this pathway stimulates megakaryocyte differentiation, enhancing platelet recovery after myelosuppressive therapy and in GATA1 deficiency.
Freson
Kathleen
K
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. kathleen.freson@med.kuleuven.be
Peeters
Karen
K
De Vos
Rita
R
Wittevrongel
Christine
C
Thys
Chantal
C
Hoylaerts
Marc F
MF
Vermylen
Jos
J
Van Geet
Chris
C
D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D045744:Cell Line, Tumor; D002887:Chromosomes, Human, Pair 18; D000242:Cyclic AMP / Q000502:physiology; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics* / Q000502:physiology; D011817:Rabbits; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000235:genetics* / Q000502:physiology; D013921:Thrombocytopenia / Q000235:genetics; D014314:Trisomy / Q000235:genetics
C495401:ADCYAP1 protein, human; D015703:Antigens, CD; D018952:Antigens, CD34; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D000242:Cyclic AMP