Calorie Restriction Increases the Number of Competing Stem Cells and Decreases Mutation Retention in the Intestine
Bruens, Lotte; Ellenbroek, Saskia Inge Johanna; Suijkerbuijk, Saskia Jacoba Elisabeth; Azkanaz, Maria; Hale, Alexander James; Toonen, Pim; Flanagan, Dustin James; Sansom, Owen James; Snippert, Hugo Johannes; van Rheenen, Jacco
(2020) Cell Reports, volume 32, issue 3, pp. 1 - 10
(Article)
Abstract
Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral
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mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine.
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Keywords: calorie restriction, competition, diet, intestine, Lgr5, mutation retention, stem cells, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: The authors would like to thank the staff at The Hubrecht Institute animal facility and the Netherlands Cancer Institute (NKI) animal facility and bioimaging facility for technical support and input and members of the van Rheenen laboratory for discussions. They would also like to thank Maartje Damen for help with the graphical abstract. This work was supported by the Netherlands Organization of Scientific Research ( NWO ) (Veni grant 863.15.011 to S.I.J.E. and Cancer Genomics Netherlands to J.v.R.), the European Research Council (consolidator grant 648804 to J.v.R.), Worldwide Cancer Research (grant 13-0297 to J.v.R.), the Dutch Cancer Society ( KWF ) (grant 2013-6070 to H.J.S.), and the Doctor Josef Steiner Foundation , Switzerland (to J.v.R.). This work was also supported by a Cancer Research UK core grant to the Beatson Institute ( A17196 ) and core funding to O.J.S. ( A21139 ). In particular, they would like to thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute. D.J.F. was funded by MRC grant MR/R017247/1 . Funding Information: The authors would like to thank the staff at The Hubrecht Institute animal facility and the Netherlands Cancer Institute (NKI) animal facility and bioimaging facility for technical support and input and members of the van Rheenen laboratory for discussions. They would also like to thank Maartje Damen for help with the graphical abstract. This work was supported by the Netherlands Organization of Scientific Research (NWO) (Veni grant 863.15.011 to S.I.J.E. and Cancer Genomics Netherlands to J.v.R.), the European Research Council (consolidator grant 648804 to J.v.R.), Worldwide Cancer Research (grant 13-0297 to J.v.R.), the Dutch Cancer Society (KWF) (grant 2013-6070 to H.J.S.), and the Doctor Josef Steiner Foundation, Switzerland (to J.v.R.). This work was also supported by a Cancer Research UK core grant to the Beatson Institute (A17196) and core funding to O.J.S. (A21139). In particular, they would like to thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute. D.J.F. was funded by MRC grant MR/R017247/1. L.B. H.J.S. and J.v.R. perceived the conceptual ideas and designed the experiments. L.B. S.I.J.E. H.J.S. and J.v.R. wrote the manuscript. L.B. S.I.J.E. S.J.E.S. M.A. A.J.H. and P.T. performed experiments. D.J.F. and O.J.S. facilitated the in situ hybridizations. The authors declare no competing interests. Publisher Copyright: © 2020 Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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