Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs
Bettina M. Moehrle,
Kalpana Nattamai,
Andreas Brown,
Maria C. Florian,
Marnie Ryan,
Mona Vogel,
Corinna Bliederhaeuser,
Karin Soller,
Daniel R. Prows,
Amir Abdollahi,
David Schleimer,
Dagmar Walter,
Michael D. Milsom,
Peter Stambrook,
Matthew Porteus,
Hartmut Geiger
Affiliations
Bettina M. Moehrle
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany
Kalpana Nattamai
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Andreas Brown
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany
Maria C. Florian
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany
Marnie Ryan
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Mona Vogel
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany
Corinna Bliederhaeuser
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany
Karin Soller
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany
Daniel R. Prows
Division of Human Genetics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Amir Abdollahi
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
David Schleimer
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Dagmar Walter
Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany
Michael D. Milsom
Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120 Heidelberg, Germany
Peter Stambrook
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
Matthew Porteus
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
Hartmut Geiger
Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany
Whether aged hematopoietic stem and progenitor cells (HSPCs) have impaired DNA damage repair is controversial. Using a combination of DNA mutation indicator assays, we observe a 2- to 3-fold increase in the number of DNA mutations in the hematopoietic system upon aging. Young and aged hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) do not show an increase in mutation upon irradiation-induced DNA damage repair, and young and aged HSPCs respond very similarly to DNA damage with respect to cell-cycle checkpoint activation and apoptosis. Both young and aged HSPCs show impaired activation of the DNA-damage-induced G1-S checkpoint. Induction of chronic DNA double-strand breaks by zinc-finger nucleases suggests that HSPCs undergo apoptosis rather than faulty repair. These data reveal a protective mechanism in both the young and aged hematopoietic system against accumulation of mutations in response to DNA damage.
