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Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons

Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 ex...

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Autores principales: Pietras, Eric M., Lakshminarasimhan, Ranjani, Techner, Jose-Marc, Fong, Sarah, Flach, Johanna, Binnewies, Mikhail, Passegué, Emmanuelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920566/
https://www.ncbi.nlm.nih.gov/pubmed/24493802
http://dx.doi.org/10.1084/jem.20131043
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author Pietras, Eric M.
Lakshminarasimhan, Ranjani
Techner, Jose-Marc
Fong, Sarah
Flach, Johanna
Binnewies, Mikhail
Passegué, Emmanuelle
author_facet Pietras, Eric M.
Lakshminarasimhan, Ranjani
Techner, Jose-Marc
Fong, Sarah
Flach, Johanna
Binnewies, Mikhail
Passegué, Emmanuelle
author_sort Pietras, Eric M.
collection PubMed
description Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 exposure. We show that IFN-1–driven HSC proliferation is a transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in response to acute IFN-1 exposure, which occurs exclusively in vivo. We find that this proliferative burst fails to exhaust the HSC pool, which rapidly returns to quiescence in response to chronic IFN-1 exposure. Moreover, we demonstrate that IFN-1–exposed HSCs with reestablished quiescence are largely protected from the killing effects of IFNs unless forced back into the cell cycle due to culture, transplantation, or myeloablative treatment, at which point they activate a p53-dependent proapoptotic gene program. Collectively, our results demonstrate that quiescence acts as a safeguard mechanism to ensure survival of the HSC pool during chronic IFN-1 exposure. We show that IFN-1s can poise HSCs for apoptosis but induce direct cell killing only upon active proliferation, thereby establishing a mechanism for the suppressive effects of IFN-1s on HSC function.
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spelling pubmed-39205662014-08-10 Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons Pietras, Eric M. Lakshminarasimhan, Ranjani Techner, Jose-Marc Fong, Sarah Flach, Johanna Binnewies, Mikhail Passegué, Emmanuelle J Exp Med Article Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 exposure. We show that IFN-1–driven HSC proliferation is a transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in response to acute IFN-1 exposure, which occurs exclusively in vivo. We find that this proliferative burst fails to exhaust the HSC pool, which rapidly returns to quiescence in response to chronic IFN-1 exposure. Moreover, we demonstrate that IFN-1–exposed HSCs with reestablished quiescence are largely protected from the killing effects of IFNs unless forced back into the cell cycle due to culture, transplantation, or myeloablative treatment, at which point they activate a p53-dependent proapoptotic gene program. Collectively, our results demonstrate that quiescence acts as a safeguard mechanism to ensure survival of the HSC pool during chronic IFN-1 exposure. We show that IFN-1s can poise HSCs for apoptosis but induce direct cell killing only upon active proliferation, thereby establishing a mechanism for the suppressive effects of IFN-1s on HSC function. The Rockefeller University Press 2014-02-10 /pmc/articles/PMC3920566/ /pubmed/24493802 http://dx.doi.org/10.1084/jem.20131043 Text en © 2014 Pietras et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Pietras, Eric M.
Lakshminarasimhan, Ranjani
Techner, Jose-Marc
Fong, Sarah
Flach, Johanna
Binnewies, Mikhail
Passegué, Emmanuelle
Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons
title Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons
title_full Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons
title_fullStr Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons
title_full_unstemmed Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons
title_short Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons
title_sort re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type i interferons
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920566/
https://www.ncbi.nlm.nih.gov/pubmed/24493802
http://dx.doi.org/10.1084/jem.20131043
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