An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion

Autor(en)

Christian Baumgartner, Stefanie Toifl, Matthias Farlik, Florian Halbritter, Ruth Scheicher, Irmgard Fischer, Veronika Sexl, Christoph Bock, Manuela Baccarini

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.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik, Department für Biochemie und Zellbiologie

Externe Organisation(en)

Veterinärmedizinische Universität Wien, Österreichische Akademie der Wissenschaften (ÖAW)

Journal

Cell Stem Cell

Band

22

Seiten

879-892.e6

Anzahl der Seiten

20

ISSN

1934-5909

DOI

https://doi.org/10.1016/j.stem.2018.05.003

Publikationsdatum

06-2018

Peer-reviewed

Ja

ÖFOS 2012

106039 Stammzellenforschung

Schlagwörter

ASJC Scopus Sachgebiete

Genetics, Molecular Medicine, Cell Biology

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/an-erkdependent-feedback-mechanism-prevents-hematopoietic-stem-cell-exhaustion(bc21ed90-8ae6-46e2-94cc-db95043d3a0e).html