CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress

Yanyan Zhang; Mallorie Dépond; Liang He; Adlen Foudi; Edward Owusu Kwarteng; Evelyne Lauret; Isabelle Plo; Christophe Desterke; Philippe Dessen; Nobutaka Fujii; Paule Opolon; Olivier Herault; Eric Solary; William Vainchenker; Virginie Joulin; Fawzia Louache; Monika Wittner

doi:10.1038/srep37827

CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress

Yanyan Zhang, Mallorie Dépond, Liang He, Adlen Foudi, Edward Owusu Kwarteng, Evelyne Lauret, Isabelle Plo, Christophe Desterke, Philippe Dessen, Nobutaka Fujii, Paule Opolon, Olivier Herault, Eric Solary, William Vainchenker, Virginie Joulin, Fawzia Louache, Monika Wittner

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72 Citations (Scopus)

Résumé

Hematopoietic stem cells (HSCs) undergo self-renewal to maintain hematopoietic homeostasis for lifetime, which is regulated by the bone marrow (BM) microenvironment. The chemokine receptor CXCR4 and its ligand CXCL12 are critical factors supporting quiescence and BM retention of HSCs. Here, we report an unknown function of CXCR4/CXCL12 axis in the protection of HSCs against oxidative stress. Disruption of CXCR4 receptor in mice leads to increased endogenous production of reactive oxygen species (ROS), resulting in p38 MAPK activation, increased DNA double-strand breaks and apoptosis leading to marked reduction in HSC repopulating potential. Increased ROS levels are directly responsible for exhaustion of the HSC pool and are not linked to loss of quiescence of CXCR4-deficient HSCs. Furthermore, we report that CXCL12 has a direct rescue effect on oxidative stress-induced HSC damage at the mitochondrial level. These data highlight the importance of CXCR4/CXCL12 axis in the regulation of lifespan of HSCs by limiting ROS generation and genotoxic stress.

langue originale	Anglais
Numéro d'article	37827
journal	Scientific Reports
Volume	6
Les DOIs	https://doi.org/10.1038/srep37827
état	Publié - 25 nov. 2016
Modification externe	Oui

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10.1038/srep37827

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Zhang, Y., Dépond, M., He, L., Foudi, A., Kwarteng, E. O., Lauret, E., Plo, I., Desterke, C., Dessen, P., Fujii, N., Opolon, P., Herault, O., Solary, E., Vainchenker, W., Joulin, V., Louache, F., & Wittner, M. (2016). CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress. Scientific Reports, 6, Article 37827. https://doi.org/10.1038/srep37827

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title = "CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress",

abstract = "Hematopoietic stem cells (HSCs) undergo self-renewal to maintain hematopoietic homeostasis for lifetime, which is regulated by the bone marrow (BM) microenvironment. The chemokine receptor CXCR4 and its ligand CXCL12 are critical factors supporting quiescence and BM retention of HSCs. Here, we report an unknown function of CXCR4/CXCL12 axis in the protection of HSCs against oxidative stress. Disruption of CXCR4 receptor in mice leads to increased endogenous production of reactive oxygen species (ROS), resulting in p38 MAPK activation, increased DNA double-strand breaks and apoptosis leading to marked reduction in HSC repopulating potential. Increased ROS levels are directly responsible for exhaustion of the HSC pool and are not linked to loss of quiescence of CXCR4-deficient HSCs. Furthermore, we report that CXCL12 has a direct rescue effect on oxidative stress-induced HSC damage at the mitochondrial level. These data highlight the importance of CXCR4/CXCL12 axis in the regulation of lifespan of HSCs by limiting ROS generation and genotoxic stress.",

author = "Yanyan Zhang and Mallorie D{\'e}pond and Liang He and Adlen Foudi and Kwarteng, {Edward Owusu} and Evelyne Lauret and Isabelle Plo and Christophe Desterke and Philippe Dessen and Nobutaka Fujii and Paule Opolon and Olivier Herault and Eric Solary and William Vainchenker and Virginie Joulin and Fawzia Louache and Monika Wittner",

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year = "2016",

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Zhang, Y, Dépond, M, He, L, Foudi, A, Kwarteng, EO, Lauret, E, Plo, I, Desterke, C, Dessen, P, Fujii, N, Opolon, P, Herault, O, Solary, E, Vainchenker, W, Joulin, V, Louache, F & Wittner, M 2016, 'CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress', Scientific Reports, VOL. 6, 37827. https://doi.org/10.1038/srep37827

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T1 - CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress

AU - Zhang, Yanyan

AU - Dépond, Mallorie

AU - He, Liang

AU - Foudi, Adlen

AU - Kwarteng, Edward Owusu

AU - Lauret, Evelyne

AU - Plo, Isabelle

AU - Desterke, Christophe

AU - Dessen, Philippe

AU - Fujii, Nobutaka

AU - Opolon, Paule

AU - Herault, Olivier

AU - Solary, Eric

AU - Vainchenker, William

AU - Joulin, Virginie

AU - Louache, Fawzia

AU - Wittner, Monika

PY - 2016/11/25

Y1 - 2016/11/25

N2 - Hematopoietic stem cells (HSCs) undergo self-renewal to maintain hematopoietic homeostasis for lifetime, which is regulated by the bone marrow (BM) microenvironment. The chemokine receptor CXCR4 and its ligand CXCL12 are critical factors supporting quiescence and BM retention of HSCs. Here, we report an unknown function of CXCR4/CXCL12 axis in the protection of HSCs against oxidative stress. Disruption of CXCR4 receptor in mice leads to increased endogenous production of reactive oxygen species (ROS), resulting in p38 MAPK activation, increased DNA double-strand breaks and apoptosis leading to marked reduction in HSC repopulating potential. Increased ROS levels are directly responsible for exhaustion of the HSC pool and are not linked to loss of quiescence of CXCR4-deficient HSCs. Furthermore, we report that CXCL12 has a direct rescue effect on oxidative stress-induced HSC damage at the mitochondrial level. These data highlight the importance of CXCR4/CXCL12 axis in the regulation of lifespan of HSCs by limiting ROS generation and genotoxic stress.

AB - Hematopoietic stem cells (HSCs) undergo self-renewal to maintain hematopoietic homeostasis for lifetime, which is regulated by the bone marrow (BM) microenvironment. The chemokine receptor CXCR4 and its ligand CXCL12 are critical factors supporting quiescence and BM retention of HSCs. Here, we report an unknown function of CXCR4/CXCL12 axis in the protection of HSCs against oxidative stress. Disruption of CXCR4 receptor in mice leads to increased endogenous production of reactive oxygen species (ROS), resulting in p38 MAPK activation, increased DNA double-strand breaks and apoptosis leading to marked reduction in HSC repopulating potential. Increased ROS levels are directly responsible for exhaustion of the HSC pool and are not linked to loss of quiescence of CXCR4-deficient HSCs. Furthermore, we report that CXCL12 has a direct rescue effect on oxidative stress-induced HSC damage at the mitochondrial level. These data highlight the importance of CXCR4/CXCL12 axis in the regulation of lifespan of HSCs by limiting ROS generation and genotoxic stress.

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