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.
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: Mallorie
authors.initials: M
authors.lastname: Dépond
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.affiliation: Paris-Saclay University, INSERM U935, Andre Lwoff Institute, Paul Brousse Hospital, Villejuif, France.
authors.forename: Adlen
authors.initials: A
authors.lastname: Foudi
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: Edward Owusu
authors.initials: EO
authors.lastname: Kwarteng
authors.affiliation: Paris Descartes University, CNRS (UMR 8104), Inserm U1016, Institut Cochin, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lauret
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.affiliation: Paris-Saclay University, UFR Medicine, INSERM UMS 33, Andre Lwoff Institute, Paul Brousse Hospital, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Desterke
authors.affiliation: Bioinformatic platform, UMS AMMICA, INSERM US23/CNRS UMS3665, Gustave Roussy, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.affiliation: Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Laboratoire de pathologie expérimentale, Gustave Roussy, Villejuif, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.affiliation: CNRS UMR 7292 GICC, Tours, France.|CNRS GDR 3697 MicroNiT, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Herault
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Joulin
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.|CNRS GDR 3697 MicroNiT, France.
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.affiliation: Paris-Saclay University, UMRS-1170, Gustave Roussy, Villejuif, France.|CNRS GDR 3697 MicroNiT, France.
authors.forename: Monika
authors.initials: M
authors.lastname: Wittner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; D048051:p38 Mitogen-Activated Protein Kinases