Thrombopoietin maintains cell numbers of hematopoietic stem and progenitor cells with megakaryopoietic potential

Thrombopoietin has long been known to influence megakaryopoiesis and hematopoietic stem and progenitor cells, although the exact mechanisms through which it acts are unknown. Here we show that MPL expression correlates with megakaryopoietic potential of hematopoietic stem and progenitor cells and identify a population of quiescent hematopoietic stem and progenitor cells that show limited dependence on thrombopoietin signaling. We show that thrombopoietin is primarily responsible for maintenance of hematopoietic cells with megakaryocytic differentiation potential and their subsequent megakaryocyte differentiation and maturation. The loss of megakaryocytes in thrombopoietin knockout mouse models results in a reduction of megakaryocyte-derived chemokine platelet factor 4 (CXCL4/PF4) in the bone marrow and administration of recombinant CXCL4/PF4 rescues the loss of quiescence observed in these mice. CXCL4/PF4 treatment does not rescue reduced hematopoietic stem and progenitor cell numbers, suggesting that thrombopoietin maintains hematopoietic stem and progenitor cell numbers directly.