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Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage
Author(s) -
Tao Si,
Tang Duozhuang,
Morita Yohei,
Sperka Tobias,
Omrani Omid,
Lechel André,
Sakk Vadim,
Kraus Johann,
Kestler Hans A,
Kühl Michael,
Rudolph Karl Lenhard
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201490700
Subject(s) - biology , wnt signaling pathway , progenitor cell , progenitor , stem cell , niche , microbiology and biotechnology , basal (medicine) , dna damage , stem cell niche , dna , genetics , biochemistry , signal transduction , endocrinology , insulin
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 ( ISPC s) to DNA damage. ISPC s at the crypt bottom with high Wnt/β‐catenin activity are more sensitive to DNA damage compared to ISPC s 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 ISPC s, 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 ISPC s to DNA damage and heterogeneity in Wnt activation in the stem cell niche contributes to the selection of ISPC s in the context of DNA damage.