title: Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage.
abstract: Aging and carcinogenesis coincide with the accumulation of DNA damage and mutations in stem and progenitor cells. Molecular mechanisms that influence responses of stem and progenitor cells to DNA damage remain to be delineated. Here, we show that niche positioning and Wnt signaling activity modulate the sensitivity of intestinal stem and progenitor cells (ISPCs) to DNA damage. ISPCs at the crypt bottom with high Wnt/β-catenin activity are more sensitive to DNA damage compared to ISPCs in position 4 with low Wnt activity. These differences are not induced by differences in cell cycle activity but relate to DNA damage-dependent activation of Wnt signaling, which in turn amplifies DNA damage checkpoint activation. The study shows that instructed enhancement of Wnt signaling increases radio-sensitivity of ISPCs, while inhibition of Wnt signaling decreases it. These results provide a proof of concept that cell intrinsic levels of Wnt signaling modulate the sensitivity of ISPCs to DNA damage and heterogeneity in Wnt activation in the stem cell niche contributes to the selection of ISPCs in the context of DNA damage.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V. (FLI), Jena, Germany Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm, Germany.
authors.forename: Si
authors.initials: S
authors.lastname: Tao
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V. (FLI), Jena, Germany.
authors.forename: Duozhuang
authors.initials: D
authors.lastname: Tang
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V. (FLI), Jena, Germany.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V. (FLI), Jena, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sperka
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V. (FLI), Jena, Germany.
authors.forename: Omid
authors.initials: O
authors.lastname: Omrani
authors.affiliation: Cooperation Group between the Leibniz Institute for Age Research, Ulm University, Ulm, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Cooperation Group between the Leibniz Institute for Age Research, Ulm University, Ulm, Germany.
authors.forename: Vadim
authors.initials: V
authors.lastname: Sakk
authors.affiliation: Medical Systems Biology Unit, Ulm University, Ulm, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Kraus
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V. (FLI), Jena, Germany Medical Systems Biology Unit, Ulm University, Ulm, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany michael.kuehl@uni-ulm.de klrudolph@fli-leibniz.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Kühl
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute e.V. (FLI), Jena, Germany Research Group on Stem Cell Aging, Jena University Hospital (UKJ), Jena, Germany michael.kuehl@uni-ulm.de klrudolph@fli-leibniz.de.
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004249:DNA Damage / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007422:Intestines / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D011836:Radiation Tolerance / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013234:Stem Cells / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
keywords: DNA damage; Wnt; intestinal progenitor cells; intestinal stem cells; telomeres