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 Blood, 15 February 2008, Vol. 111, No. 4, pp. 1885-1893.
Prepublished online as a Blood First Edition Paper on November 13, 2007; DOI 10.1182/blood-2007-06-098558.

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HEMATOPOIESIS

PACAP and its receptor VPAC1 regulate megakaryocyte maturation: therapeutic implications

Kathleen Freson1, Karen Peeters1, Rita De Vos2, Christine Wittevrongel1, Chantal Thys1, Marc F. Hoylaerts1, Jos Vermylen1, and Chris Van Geet1,3

1 Center for Molecular and Vascular Biology, University of Leuven, 2 Department of Pathology, and 3 Department of Pediatrics, University of Leuven, Leuven, Belgium

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.


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Related Article in Blood Online:

PACAP: a new player in thrombopoiesis
Jorge Di Paola
Blood 2008 111: 1753-1754. [Full Text] [PDF]





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