Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation
Oral and Poster Abstracts
504. Hematopoiesis: Cytokines, Signal Transduction, Apoptosis and Cell Cycle Regulation: Poster II
Hall A, Level 2
(Orange County Convention Center)
Simon Haas1,2*, Jenny Hansson3,4*, Daniel Klimmeck1,2,4*, Dirk Loeffler5*, Lars Velten4*, Hannah Uckelmann1,6*, Stephan Wurzer1,2*, Áine M. Prendergast, PhD1,2*, Alexandra Schnell1,2*, Klaus Hexel1*, Rachel Santarella-Mellwig4*, Sandra Blaszkiewicz1,2*, Andrea Kuck1,2*, Hartmut Geiger, PhD7,8, Michael D. Milsom, PhD1,9, Lars M Steinmetz4,10,11*, Timm Schroeder, PhD12*, Andreas Trumpp, PhD9,13*, Jeroen Krijgsveld4* and Marieke A. G. Essers, PhD1,2
1German Cancer Research Center (DKFZ), Heidelberg, Germany
2Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
3Lund Stem Cell Center, Lund, Sweden
4EMBL, Heidelberg, Germany
5ETH Zurich, Basel, Switzerland
6Heidelberg Institute for Stem Cell Technologies and Experimental medicine (HI-STEM), Heidelberg, Germany
7Institute of Molecular Medicine, Ulm University, Ulm, Germany
8Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
9HI-STEM, Heidelberg, Germany
10Stanford Genome Technology Center, Palo Alto
11Department of Genetics, Stanford University School of Medicine, Stanford
12Department of Biosystems Science and Engineering (D-BSSE), Swiss Federal Institute of Technology (ETH) Zürich, Basel, Switzerland
13Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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.
Disclosures: No relevant conflicts of interest to declare.
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