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

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