Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age

Abstract

A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of ageing. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to ageing1. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline2. We have tested these hypotheses by examining haematopoietic stem cell reserves and function with age in mice deficient in several genomic maintenance pathways including nucleotide excision repair3,4, telomere maintenance5,6 and non-homologous end-joining7,8. Here we show that although deficiencies in these pathways did not deplete stem cell reserves with age, stem cell functional capacity was severely affected under conditions of stress, leading to loss of reconstitution and proliferative potential, diminished self-renewal, increased apoptosis and, ultimately, functional exhaustion. Moreover, we provide evidence that endogenous DNA damage accumulates with age in wild-type stem cells. These data are consistent with DNA damage accrual being a physiological mechanism of stem cell ageing that may contribute to the diminished capacity of aged tissues to return to homeostasis after exposure to acute stress or injury.

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Figure 1: Stem and progenitor reserves with age in genomic maintenance-deficient mice.
Figure 2: Telomerase-deficiency limits LT-HSC function with age.
Figure 3: NER deficiency limits LT-HSC function with age.
Figure 4: NHEJ deficiency and endogenous damage accumulation in stem cells with age.

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Acknowledgements

We thank D. Bhattacharya for critical reading of the manuscript. A.N. was supported by NCI’s Center for Cancer Research. D.J.R. was supported by the Damon Runyon Cancer Foundation and the California Institute of Regenerative Medicine. D.B. was supported by a Swedish Medical Research Council scholarship (STINT) and a Cancerfonden grant.

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Correspondence to Derrick J. Rossi.

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Rossi, D., Bryder, D., Seita, J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007). https://doi.org/10.1038/nature05862

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