The Mpl receptor expressed on endothelial cells does not contribute significantly to the regulation of circulating thrombopoietin levels

Blood levels of thrombopoietin (TPO) are regulated in part by cellular degradation following its binding to the cell surface receptor c-mpl. Previous reports have demonstrated that in addition to hematopoietic cells, c-mpl is expressed on and functions in several types of endothelial cells (ECs). We hypothesized that the c-mpl expressed on ECs would contribute to the regulation of circulating TPO levels. To test this hypothesis we transplanted c-mpl-null and wild-type (WT) control mice with WT marrow stem cells, resulting in two groups of posttransplant chimeric animals, one expressing c-mpl on megakaryocytes and platelets only and one in which the receptor is expressed on both hematopoietic and ECs. Should EC c-mpl take up TPO and degrade it, we predicted that c-mpl-null mice reconstituted with WT cells would display increased TPO levels and an increased steady state platelet count compared to the WT recipients. Contrary to our prediction, for up to 6 months posttransplantation both platelet counts and TPO levels in both groups of transplanted mice were virtually identical. Our results indicate that the EC c-mpl receptor does not contribute significantly to the regulation of TPO levels or to steady-state platelet counts. These results also imply that patients with congenital amegakaryocytic thrombocytopenia, lacking the c-mpl receptor, who have successfully been engrafted with normal hematopoietic stem cells should have normal (not elevated) TPO levels and that gene replacement strategies designed to restore c-mpl in these patients do not need to target ECs to establish the normal regulation of TPO.