Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors

• Published in: Cell stem cell Vol. 17; no. 4; pp. 422 - 434
• Main Authors: Haas, Simon, Hansson, Jenny, Klimmeck, Daniel, Loeffler, Dirk, Velten, Lars, Uckelmann, Hannah, Wurzer, Stephan, Prendergast, Áine M., Schnell, Alexandra, Hexel, Klaus, Santarella-Mellwig, Rachel, Blaszkiewicz, Sandra, Kuck, Andrea, Geiger, Hartmut, Milsom, Michael D., Steinmetz, Lars M., Schroeder, Timm, Trumpp, Andreas, Krijgsveld, Jeroen, Essers, Marieke A.G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015
• Subjects: Animals; Blood Platelets - pathology; Blood Platelets - physiology; Cell Lineage; Cell Proliferation; Hematopoietic Stem Cells - pathology; Hematopoietic Stem Cells - physiology; Inflammation - pathology; Megakaryocyte Progenitor Cells - pathology; Megakaryocyte Progenitor Cells - physiology; Mice; Thrombopoiesis
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2015.07.007

Infections are associated with extensive platelet consumption, representing a high risk for health. However, the mechanism coordinating the rapid regeneration of the platelet pool during such stress conditions remains unclear. Here, we report that the phenotypic hematopoietic stem cell (HSC) compartment contains stem-like megakaryocyte-committed progenitors (SL-MkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammatory insults. During homeostasis, SL-MkPs are maintained in a primed but quiescent state, thus contributing little to steady-state megakaryopoiesis. Even though lineage-specific megakaryocyte transcripts are expressed, protein synthesis is suppressed. In response to acute inflammation, SL-MkPs become activated, resulting in megakaryocyte protein production from pre-existing transcripts and a maturation of SL-MkPs and other megakaryocyte progenitors. This results in an efficient replenishment of platelets that are lost during inflammatory insult. Thus, our study reveals an emergency machinery that counteracts life-threatening platelet depletions during acute inflammation. [Display omitted] •Unipotent SL-MkPs are maintained in a quiescent, but primed, state during homeostasis•Inflammation instructs post-transcriptional Mk protein synthesis in SL-MkPs•Inflammation drives efficient cell cycle activation and maturation of SL-MkPs•Activation of SL-MkPs rapidly replenishes the platelet pool during acute inflammation Haas et al. show that inflammatory signaling activates post-transcriptional protein synthesis, maturation, and cell cycle induction in quiescent, but primed, stem-like megakaryocyte progenitors. This emergency program efficiently prevents otherwise life-threatening platelet depletion during acute inflammation.