Zeitschriftenaufsatz
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2018
An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion
Autor:in
Baumgartner, Christian; Toifl, Stefanie; Farlik, Matthias; Halbritter, Florian; Scheicher, Ruth; Fischer, Irmgard; Sexl, Veronika; Bock, Christoph; Baccarini, Manuela
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
Hematopoietic stem cells (HSCs) sustain hematopoiesis throughout life. HSCs exit dormancy to restore hemostasis in response to stressful events, such as acute blood loss, and must return to a quiescent state to prevent their exhaustion and resulting bone marrow failure. HSC activation is driven in part through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTORC1 signaling pathway, but less is known about the cell-intrinsic pathways that control HSC dormancy. Here, we delineate an ERK-dependent, rate-limiting feedback mechanism that controls HSC fitness and their re-entry into quiescence. We show that the MEK/ERK and PI3K pathways are synchronously activated in HSCs during emergency hematopoiesis and that feedback phosphorylation of MEK1 by activated ERK counterbalances AKT/mTORC1 activation. Genetic or chemical ablation of this feedback loop tilts the balance between HSC dormancy and activation, increasing differentiated cell output and accelerating HSC exhaustion. These results suggest that MEK inhibitors developed for cancer therapy may find additional utility in controlling HSC activation.
Schlagwörter
Animals; Cells, Cultured; Coculture Techniques; Extracellular Signal-Regulated MAP Kinasesmetabolism; Female; Hematopoietic Stem Cellscytologyenzymology; Humans; MAP Kinase Kinase 1deficiencymetabolism; Male; Membrane Potential, Mitochondrial; Mice; Reactive Oxygen Speciesmetabolism
Dokumententyp
Originalarbeit
CC Lizenz
CCBYNCND
Open Access Type
Hybrid
ISSN/eISSN
1934-5909 - 1875-9777
10.1016/j.stem.2018.05.003
WoS ID
PubMed ID