The Molecular Mechanisms of Serotonin in the Regulation of Megakaryocytopoiesis and TPO Production

Abstract 3347

We have reported that serotonin (5-HT) show a promoting effect on cord blood CD34⁺ stem/progenitor cells (Yang et al, Stem Cells 2007). We also demonstrated that serotonin enhances murine megakaryopoiesis via 5-HT₂ receptors (Yang et al. Blood Coagul Fibrinol 1996). In this present study, we explored how serotonin regulated human megakaryocytopoiesis, proplatelet formation, and thrombopoietin (TPO) production. Our results indicated that serotonin significantly promoted human CFU-MK formation and reduced apoptosis in megakaryocytes through phosphorylation of Akt. These effects were attenuated by addition of ketanserin, a 5-HT₂ receptor inhibitor. In addition, serotonin was able to stimulate the F-actin reorganization in megakaryocytes through activating the p-Erk1/2 expression. Bone marrow mesenchymal stromal cells (MSCs) are important in regulating megakaryocytopoiesis through stimulating release of thrombopoietic growth factor, such as TPO. Our studies suggested that when activated by serotonin, bone marrow MSCs were induced to release significant amount of TPO by q-PCR, ELISA and cytokine-array assays. Our findings demonstrated an important role of serotonin played on megakaryocytopoiesis. This effect was likely mediated via 5HT₂ receptors with subsequent activation of Akt and Erk 1/2 phosphorylation, which led to survival of megakaryocytes and proplatelet formation. Serotonin also stimulated TPO released from MSCs, which indirectly promoted megakaryopoiesis. In present studies, we have demonstrated a positive “feed-back” control loop between MK-derived granule- serotonin and megakaryocytopoiesis. These findings improved our knowledge on megakaryocytopoiesis regulation and provided new clues on identifying novel thrombopoietic agents. It also deepened our understandings on how TPO production is regulated.