Publication Date:
2015-02-25
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Walter, Dagmar -- Lier, Amelie -- Geiselhart, Anja -- Thalheimer, Frederic B -- Huntscha, Sina -- Sobotta, Mirko C -- Moehrle, Bettina -- Brocks, David -- Bayindir, Irem -- Kaschutnig, Paul -- Muedder, Katja -- Klein, Corinna -- Jauch, Anna -- Schroeder, Timm -- Geiger, Hartmut -- Dick, Tobias P -- Holland-Letz, Tim -- Schmezer, Peter -- Lane, Steven W -- Rieger, Michael A -- Essers, Marieke A G -- Williams, David A -- Trumpp, Andreas -- Milsom, Michael D -- England -- Nature. 2015 Apr 23;520(7548):549-52. doi: 10.1038/nature14131. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany. ; Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, Experimental Hematology Group, 69120 Heidelberg, Germany. ; LOEWE Center for Cell and Gene Therapy and Department of Hematology/Oncology, Goethe University Frankfurt, 60595 Frankfurt am Main, Germany. ; Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Division of Redox Regulation, 69120 Heidelberg, Germany. ; Institute for Molecular Medicine, Stem Cells and Aging, Ulm University, 89081 Ulm, Germany. ; Deutsches Krebsforschungszentrum (DKFZ), Division of Stem Cells and Cancer, 69120 Heidelberg, Germany. ; Institute of Human Genetics, University of Heidelberg, 69120 Heidelberg, Germany. ; ETH Zurich, Department of Biosystems Science and Engineering, 4058 Basel, Switzerland. ; 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. ; Deutsches Krebsforschungszentrum (DKFZ), Division of Biostatistics, 69120 Heidelberg, Germany. ; Deutsches Krebsforschungszentrum (DKFZ), Division of Epigenomics and Cancer Risk Factors, 69120 Heidelberg, Germany. ; QIMR Berghofer Medical Research Institute, University of Queensland, Brisbane 4006, Australia. ; 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. ; 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. ; 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707806" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bone Marrow/pathology
;
*Cell Cycle
;
Cell Death
;
Cell Proliferation
;
*DNA Damage
;
Fanconi Anemia/metabolism
;
Hematopoietic Stem Cells/*cytology/*metabolism
;
Mice
;
Reactive Oxygen Species/metabolism
;
Stress, Physiological
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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