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DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival

Hematopoietic stem cells (HSCs) maintain blood cell production life‐long by their unique abilities of self‐renewal and differentiation into all blood cell lineages. Growth arrest and DNA‐damage‐inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell c...

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Autores principales: Wingert, Susanne, Thalheimer, Frederic B., Haetscher, Nadine, Rehage, Maike, Schroeder, Timm, Rieger, Michael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832267/
https://www.ncbi.nlm.nih.gov/pubmed/26731607
http://dx.doi.org/10.1002/stem.2282
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author Wingert, Susanne
Thalheimer, Frederic B.
Haetscher, Nadine
Rehage, Maike
Schroeder, Timm
Rieger, Michael A.
author_facet Wingert, Susanne
Thalheimer, Frederic B.
Haetscher, Nadine
Rehage, Maike
Schroeder, Timm
Rieger, Michael A.
author_sort Wingert, Susanne
collection PubMed
description Hematopoietic stem cells (HSCs) maintain blood cell production life‐long by their unique abilities of self‐renewal and differentiation into all blood cell lineages. Growth arrest and DNA‐damage‐inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell cycle control, cell death and senescence, as well as in DNA‐damage repair. In general, GADD45A provides cellular stability by either arresting the cell cycle progression until DNA damage is repaired or, in cases of fatal damage, by inducing apoptosis. However, the function of GADD45A in hematopoiesis remains controversial. We revealed the changes in murine HSC fate control orchestrated by the expression of GADD45A at single cell resolution. In contrast to other cellular systems, GADD45A expression did not cause a cell cycle arrest or an alteration in the decision between cell survival and apoptosis in HSCs. Strikingly, GADD45A strongly induced and accelerated the differentiation program in HSCs. Continuous tracking of individual HSCs and their progeny via time‐lapse microscopy elucidated that once GADD45A was expressed, HSCs differentiate into committed progenitors within 29 hours. GADD45A‐expressing HSCs failed to long‐term reconstitute the blood of recipients by inducing multilineage differentiation in vivo. Importantly, γ‐irradiation of HSCs induced their differentiation by upregulating endogenous GADD45A. The differentiation induction by GADD45A was transmitted by activating p38 Mitogen‐activated protein kinase (MAPK) signaling and allowed the generation of megakaryocytic‐erythroid, myeloid, and lymphoid lineages. These data indicate that genotoxic stress‐induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. Stem Cells 2016;34:699–710
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spelling pubmed-48322672016-04-20 DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival Wingert, Susanne Thalheimer, Frederic B. Haetscher, Nadine Rehage, Maike Schroeder, Timm Rieger, Michael A. Stem Cells Tissue‐Specific Stem Cells Hematopoietic stem cells (HSCs) maintain blood cell production life‐long by their unique abilities of self‐renewal and differentiation into all blood cell lineages. Growth arrest and DNA‐damage‐inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell cycle control, cell death and senescence, as well as in DNA‐damage repair. In general, GADD45A provides cellular stability by either arresting the cell cycle progression until DNA damage is repaired or, in cases of fatal damage, by inducing apoptosis. However, the function of GADD45A in hematopoiesis remains controversial. We revealed the changes in murine HSC fate control orchestrated by the expression of GADD45A at single cell resolution. In contrast to other cellular systems, GADD45A expression did not cause a cell cycle arrest or an alteration in the decision between cell survival and apoptosis in HSCs. Strikingly, GADD45A strongly induced and accelerated the differentiation program in HSCs. Continuous tracking of individual HSCs and their progeny via time‐lapse microscopy elucidated that once GADD45A was expressed, HSCs differentiate into committed progenitors within 29 hours. GADD45A‐expressing HSCs failed to long‐term reconstitute the blood of recipients by inducing multilineage differentiation in vivo. Importantly, γ‐irradiation of HSCs induced their differentiation by upregulating endogenous GADD45A. The differentiation induction by GADD45A was transmitted by activating p38 Mitogen‐activated protein kinase (MAPK) signaling and allowed the generation of megakaryocytic‐erythroid, myeloid, and lymphoid lineages. These data indicate that genotoxic stress‐induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. Stem Cells 2016;34:699–710 John Wiley and Sons Inc. 2016-01-26 2016-03 /pmc/articles/PMC4832267/ /pubmed/26731607 http://dx.doi.org/10.1002/stem.2282 Text en © 2016 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press This is an open access article under the terms of the Creative Commons Attribution‐NoDerivs (http://creativecommons.org/licenses/by-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made.
spellingShingle Tissue‐Specific Stem Cells
Wingert, Susanne
Thalheimer, Frederic B.
Haetscher, Nadine
Rehage, Maike
Schroeder, Timm
Rieger, Michael A.
DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
title DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
title_full DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
title_fullStr DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
title_full_unstemmed DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
title_short DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
title_sort dna‐damage response gene gadd45a induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
topic Tissue‐Specific Stem Cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832267/
https://www.ncbi.nlm.nih.gov/pubmed/26731607
http://dx.doi.org/10.1002/stem.2282
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