Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage

作者：Si Tao, Duozhuang Tang, Yohei Morita, Tobias Sperka, Omid Omrani, André Lechel, Vadim Sakk, Johann M. Kraus, Hans A. Kestler, Michael Kühl, K. Lenhard Rudolph · 发表于：The EMBO Journal · 年份：2015 · DOI：10.15252/embj.201490700 · 被引用次数：95 · 研究领域：Epigenetics and DNA Methylation、DNA Repair Mechanisms、Digestive system and related health

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. New genetic results suggest that DNA damage‐induced modulation of Wnt signaling determines radio‐sensitivity of intestinal stem‐ and progenitor cells. New genetic results suggest that DNA damage‐induced modulation of Wnt signaling determines radio‐sensitivity of intestinal stem‐ and progenitor cells.