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An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion
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 p...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988582/ https://www.ncbi.nlm.nih.gov/pubmed/29804890 http://dx.doi.org/10.1016/j.stem.2018.05.003 |
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author | Baumgartner, Christian Toifl, Stefanie Farlik, Matthias Halbritter, Florian Scheicher, Ruth Fischer, Irmgard Sexl, Veronika Bock, Christoph Baccarini, Manuela |
author_facet | Baumgartner, Christian Toifl, Stefanie Farlik, Matthias Halbritter, Florian Scheicher, Ruth Fischer, Irmgard Sexl, Veronika Bock, Christoph Baccarini, Manuela |
author_sort | Baumgartner, Christian |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5988582 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-59885822018-06-06 An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion Baumgartner, Christian Toifl, Stefanie Farlik, Matthias Halbritter, Florian Scheicher, Ruth Fischer, Irmgard Sexl, Veronika Bock, Christoph Baccarini, Manuela Cell Stem Cell Article 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. Cell Press 2018-06-01 /pmc/articles/PMC5988582/ /pubmed/29804890 http://dx.doi.org/10.1016/j.stem.2018.05.003 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Baumgartner, Christian Toifl, Stefanie Farlik, Matthias Halbritter, Florian Scheicher, Ruth Fischer, Irmgard Sexl, Veronika Bock, Christoph Baccarini, Manuela An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion |
title | An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion |
title_full | An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion |
title_fullStr | An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion |
title_full_unstemmed | An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion |
title_short | An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion |
title_sort | erk-dependent feedback mechanism prevents hematopoietic stem cell exhaustion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988582/ https://www.ncbi.nlm.nih.gov/pubmed/29804890 http://dx.doi.org/10.1016/j.stem.2018.05.003 |
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