Model for the regulation of megakaryopoiesis and platelet numbers by Tpo. (A) Normal steady-state situation. Tpo (blue circles) is produced in the liver at a constant rate and reaches the bone marrow via the blood stream. Tpo enters the bone marrow microenvironment and binds to its receptor, Mpl (drawn in red), that is expressed on HSCs and megakaryocytic progenitors. Signaling requires the presence of Jak2 (green circles) and results in expansion of the HSCs and megakaryocytic progenitor pool. The megakaryocytic differentiation and polyploidization begins at the stage of promegakaryoblasts (pro-Meg) and ends with fully differentiated megakaryocytes (Meg), which deliver platelets (PLT) to the lumen of the blood vessels (yellow arrow). The bone marrow cells that express Mpl and platelets bind, internalize, and degrade Tpo, thereby lowering the available Tpo. (B) Megakaryocyte and platelet-specific knockout of Jak2. Expression of Cre-recombinase driven by the Pf4 regulatory elements begins in late megakaryocytic progenitors and deletes Jak2 in megakaryocytes and platelets. Mpl expression remains normal throughout megakaryopoiesis, but Tpo cannot signal in late megakaryopoetic cells or platelets. Mpl without Jak2 cannot efficiently remove and degrade Tpo. As a consequence, more Tpo is available in the bone marrow, leading to an expansion of HSCs, early megakaryocyte-biased progenitors, and colony-forming unit Meg. Thrombocytosis is observed in the peripheral blood.