|
| Status |
Public on May 28, 2018 |
| Title |
A system of checks and balances: an ERK-dependent feedback mechanism prevents hematopoietic stem cell exhaustion |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Hematopoietic stem cells (HSC) sustain hematopoiesis throughout life, exiting dormancy to replenish homeostatic or acute cell loss in the peripheral blood. HSC activation is supported by PI3-Kinase/AKT/mTORC1 pathway, which promotes mitochondrial expansion, oxidative phosphorylation, and reactive oxygen species production. Activated HSCs must return to dormancy to prevent exhaustion and bone marrow failure, but the cell-intrinsic mechanisms underlying this transition are unknown. Here we identify an ERK-dependent, rate-limiting feedback mechanism that controls the fitness of the HSC compartment. We show that the MEK/ERK and PI3-Kinase pathways are synchronously deployed in HSC during emergency hematopoiesis, and that feedback phosphorylation of MEK1 by activated ERK is required to constrain AKT/mTORC1 activation. Genetic or chemical ablation of this feedback tilts the balance between HSC dormancy and activation, increasing the output of differentiated cells and accelerating HSC exhaustion. MEK inhibitors developed for cancer therapy may thus be useful to modulate HSC activation.
|
| |
|
| Overall design |
RNA-seq: WT (n=3+1 technical) vs. KO (n=3) HSCs + 5-FU-treated WT (n=4) vs. KO (n=3) HSCs; 13 RNA-seq datasets total
|
| Web link |
https://0-doi-org.brum.beds.ac.uk/10.1016/j.stem.2018.05.003
|
| |
|
| Contributor(s) |
Baumgartner C, Toifl S, Farlik M, Halbritter F, Scheicher R, Fischer I, Sexl V, Bock C, Baccarini M |
| Citation(s) |
29804890 |
| Submission date |
Apr 09, 2018 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Christoph Bock |
| E-mail(s) |
cbock@cemm.oeaw.ac.at
|
| Organization name |
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
|
| Street address |
Lazarettgasse 14
|
| City |
Vienna |
| ZIP/Postal code |
1090 |
| Country |
Austria |
| |
|
| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
|
| Samples (13)
|
|
| Relations |
| BioProject |
PRJNA449288 |
Less...
More...