The Fanconi anemia pathway is required for efficient repair of stress-induced DNA damage in haematopoietic stem cells

Abstract

Within regenerating tissues, aging is characterized by a progressive general deterioration of organ function, thought to be driven by the gradual depletion of functional adult stem cells. Although there are probably multifactorial mechanisms that result in compromized stem cell functionality with advancing age, the accumulation of DNA damage within the stem cell compartment is likely to make a major contribution to this process. However, the physiologic source of DNA damage within the different tissue specific stem cell compartments remains to be determined, as does the fate of stem cells exposed to such damage. Using the haematopoietic system as a model organ, we have recently shown that certain forms of physiologic stress, such as infection-associated inflammation and extensive blood loss, leads to the induction of biologically relevant levels of DNA damage in haematopoietic stem cells (HSCs) by dramatically increasing the proliferative index of this normally quiescent cell population.¹ We were also able to demonstrate that such stress-associated DNA damage was sufficient to completely deplete HSCs and promote severe aplastic anemia (SAA) in the Fanconi anemia (FA) knockout mouse model, which has compromized replication-associated DNA repair. In this “Extra Views” article, we extend this previous work to show that FA mice do not spontaneously develop a haematopoietic phenotype consistent with SAA, even at extreme old age. This suggests that HSC quiescence restricts the acquisition of DNA damage during aging and preserves the functional integrity of the stem cell pool. In line with this hypothesis, we provide an extended time course analysis of the response of FA knockout mice to chronic inflammatory stress and show that enforced HSC proliferation leads to a highly penetrant SAA phenotype, which closely resembles the progression of the disease in FA patients.

Keywords:

• aging
• aplastic anemia
• bone marrow failure
• cell cycle
• DNA damage
• Fanconi anemia
• Haematopoietic stem cells
• inflammation
• quiescence
• stress

Funding

DW, AL and MDM were supported by the BioRN Leading-Edge Cluster “Cell-Based and Molecular Medicine” funded by the German Federal Ministry of Education and Research, and the Dietmar Hopp Foundation. PK was funded by a fellowship from the Helmholtz International Graduate School and RB by a post-doctoral fellowship from the DKFZ.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank the Animal Laboratory Services Deutsches Krebsforschungszentrum (DKFZ) Core Facility and the Imaging and Cytometry DKFZ Core Facility, in particular Ann Atzberger and Klaus Hexel. We would also like to express our gratitude to Vanessa Vogel for technical support.