Quantitative proteomics of Hematopoietic Stem Cells during acute inflammation

Infections are associated with extensive consumption of blood platelets representing a high risk for health. How the hematopoietic system coordinates the rapid and efficient regeneration of this particular lineage during such stress scenarios remains unclear. Here we report that the phenotypic hematopoietic stem cell (HSC) compartment contains highly potent megakaryocyte-committed progenitors (hipMkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammatory insults. Our data show that during homeostasis, hipMkPs are maintained in a primed but quiescent state, thus contributing little to steady-state megakaryopoiesis. Moreover, homeostatic hipMkPs show expression of megakaryocyte lineage priming transcripts for which protein synthesis is suppressed. We demonstrate that acute inflammatory signaling instructs activation of hipMkPs, as well as Mk protein production from pre-existing transcripts and drives a rapid maturation of hipMkPs and other Mk progenitors. This results in an efficient regeneration of platelets that are lost during inflammatory insult. Thus, our study reveals an elegant emergency machinery that counteracts life-threating depletions in the platelet pool during acute inflammation.