Stem Cell-like Megakaryocyte Progenitors As Driving Forces of IFN-Induced Emergency Megakaryopooesis

Abstract

Recent reports have highlighted the importance of platelets as inflammatory and immune cells in addition to their well-known function in thrombosis. Systemic inflammation associated with acute infection triggers the release of immune-modulatory agents and the interaction of platelets with neutrophils to facilitate the formation of neutrophil extracellular traps (NETs). This provokes a rapid consumption of platelets resulting in a transient thrombocytopenia. During acute inflammation, low platelet levels are associated with a loss of vascular integrity and hemorrhage, as well as septic shock resulting in increased mortality. Therefore, a fast recovery of platelet levels is essential. However, the exact mechanism by which platelet levels are rapidly regenerated after acute inflammation remains unknown.Here, we show that inflammatory signaling instructs a rapid Mk maturation program at distinct levels of megakaryopoiesis to regenerate the lost platelet pool. While megakaryocyte progenitors (MkPs) are efficiently driven into endomitosis leading to a strong increase in mature Mks, a small pool of potent stem-like megakaryocyte-committed progenitors (SL-MkPs) within the phenotypic HSC compartment replaces the lost MkPs. Type I Interferon (IFN) signaling triggers FoxO3a inactivation, resulting in cell cycle activation of these normally quiescent SL-MkPs. Moreover, IFN signaling mediates a rapid functional and cellular maturation program of SL-MkPs, associated with mTOR and STAT1 dependent increase in cell size, enhanced Mk protein production and appearance of alpha granular precursors.Interestingly, while acute inflammatory signaling drives rapid maturation of Mk progenitors resulting in increased platelet production, repeated cycles of type-I IFN mediated inflammation triggers a constant push of maturation and thus leads to a partial exhaustion of Mk progenitors. These findings reveal that depending on the context and timing, the same IFN stimulus can be associated with opposing effects on megakaryopoiesis. This may explain why some inflammatory states are associated with thrombocytosis, while others provoke thrombocytopenia. DisclosuresNo relevant conflicts of interest to declare.