Hematopoietic stem cells (HSCs) sustain blood and immune cells in the body and are therefore crucial for our survival. HSCs are at rest, but as soon as blood needs to be formed - like after blood loss or chemotherapy - they are quickly activated to compensate for this loss. After completing their mission, they must return a dormant state. A team of scientists, including Christoph Bock (CeMM) and Veronika Sexl (Vetmeduni Vienna) – lead by Manuela Baccarini (Max F. Perutz Laboratories (MFPL)) – has now shown how intracellular signal transmissions can maintain this delicate balance between activation and dormancy.
The switch between HSC active and inactive states requires a precisely regulated balance. It was already known that HSC activation is driven in part through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTORC1 signaling pathway, but less was known about the cell-intrinsic pathways that control HSC dormancy. In this study, the researchers were able to describe in detail the intracellular networks responsible for this balance. The authors show that the MEK/ERK and PI3K pathways are synchronously activated in HSCs during emergency hematopoiesis. Importantly, they show that the feedback phosphorylation of MEK1 by activated ERK counterbalances AKT/mTORC1 activation and that the MEK1 phosphorylation returns activated HSCs to quiescence. Overall, these results suggest a new role for the MEK/ERK pathway in hematopoiesis and that MEK inhibitors currently used for cancer therapy may find additional utility in controlling HSC activation.
Publication in Cell Stem Cell
Christian Baumgartner, Stefanie Toifl, Matthias Farlik, Florian Halbritter, Ruth Scheicher, Irmgard Fischer, Veronika Sexl, Christoph Bock and Manuela Baccarini