title: Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells.
abstract: Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Walter
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Lier
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Experimental Hematology Group, 69120 Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Geiselhart
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Hematology/Oncology, Goethe University Frankfurt, 60595 Frankfurt am Main, Germany.
authors.forename: Frederic B
authors.initials: FB
authors.lastname: Thalheimer
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Huntscha
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Division of Redox Regulation, 69120 Heidelberg, Germany.
authors.forename: Mirko C
authors.initials: MC
authors.lastname: Sobotta
authors.affiliation: Institute for Molecular Medicine, Stem Cells and Aging, Ulm University, 89081 Ulm, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Moehrle
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Experimental Hematology Group, 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Brocks
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Experimental Hematology Group, 69120 Heidelberg, Germany.
authors.forename: Irem
authors.initials: I
authors.lastname: Bayindir
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Experimental Hematology Group, 69120 Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Kaschutnig
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, 69120 Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Muedder
authors.affiliation: Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Klein
authors.affiliation: Institute of Human Genetics, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: ETH Zurich, Department of Biosystems Science and Engineering, 4058 Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: 1] Institute for Molecular Medicine, Stem Cells and Aging, Ulm University, 89081 Ulm, Germany [2] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Division of Redox Regulation, 69120 Heidelberg, Germany.
authors.forename: Tobias P
authors.initials: TP
authors.lastname: Dick
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Division of Biostatistics, 69120 Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Holland-Letz
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Division of Epigenomics and Cancer Risk Factors, 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: QIMR Berghofer Medical Research Institute, University of Queensland, Brisbane 4006, Australia.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Hematology/Oncology, Goethe University Frankfurt, 60595 Frankfurt am Main, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.affiliation: 1] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany [2] Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Hematopoietic Stem Cells and Stress Group, 69120 Heidelberg, Germany.
authors.forename: Marieke A G
authors.initials: MA
authors.lastname: Essers
authors.affiliation: 1] Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Dana-Faber Cancer Institute, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Boston, Massachusetts 02138, USA [4] Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: 1] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany [2] Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: 1] Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany [2] Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Experimental Hematology Group, 69120 Heidelberg, Germany.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Milsom
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002453:Cell Cycle; D016923:Cell Death; D049109:Cell Proliferation; D004249:DNA Damage; D005199:Fanconi Anemia / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D017382:Reactive Oxygen Species