Objective: 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.
Methods: 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.
Results: 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.
Conclusions: 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.