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

Abstract

The authors state that it came to their attention that the figure legends of two figures were not sufficiently detailed in the original version of the manuscript.The figure Representative Western blots of cell lysates for the expression of phospho-p53 and cleaved caspase-3 (each n = 3; see Source Data for this figure). Samples from a single experiment were divided into identical portions and probed for phospho-p53 or cleaved casp3. The expression control of beta-actin was conducted on the second aliquot of the samples and was run in parallel on a separate gel.The corrections do not affect the original conclusions presented. We apologize for the lack of detail and any inconvenience it may have caused. Editorial NoteThese changes were based on the results of an investigation of the Leibniz Association. All authors agree with this correction.

Reserve Stem Cells in Intestinal Homeostasis and Injury

“…In this situation, Lgr5-expressing ISCs were particularly susceptible to radiation exposure, and could be almost completely ablated by high doses of radiation. 30,62,63 In contrast, Bmi1-expressing ISCs were not only radio-resistant, but lineage tracing output increased after exposure to radiation, 30 indicating that the þ4 quiescent ISCs were at least partly responsible for the regenerative response. In addition to cells that express Bmi1, 30 cell populations that express Hopx, 57,64,65 mouse Tert, 59,66 and other genes 63,[67][68][69] were found to have regenerative, ISC functions after epithelial damage, supporting a model in which quiescent þ4 ISCs can survive and participate in regeneration after loss of aISCs.…”

High Canonical Wnt/β-Catenin Activity Sensitizes Murine Hematopoietic Stem and Progenitor Cells to DNA Damage

“…However, Tao et al have also shown that niche positioning determines the Wnt signaling activity of intestinal stem and progenitor cells (ISPCs), with ISPCs at the intestinal crypt bottom exhibiting higher Wnt/−catenin activity than the ISPCs located at higher positions of the crypt. ISPCs with higher Wnt signaling activity are preferentially depleted by irradiation-induced DNA damage [18]. Furthermore, instructed enhancement of Wnt signaling increases radio-sensitivity of ISPCs, while inhibition of Wnt signaling decreases it [18].…”

“…ISPCs with higher Wnt signaling activity are preferentially depleted by irradiation-induced DNA damage [18]. Furthermore, instructed enhancement of Wnt signaling increases radio-sensitivity of ISPCs, while inhibition of Wnt signaling decreases it [18]. These seemingly contradictory results from different studies on the role of Wnt signaling activity on fate and activities of ISPCs upon DNA damage might due to the different angles of the studies: Tao et al particularly looked at the early fate (i.e.…”

“…Preferential maintenance of HSPCs with low Wntsignaling activity in response to DNA damage could influence clonal drifts and the selection of aberrant stem cells during aging and carcinogenesis. Although over-activation of Wntsignaling leads to exhaustion of non-transformed stem cells [12][13][14]18], activation of Wnt-signaling has been frequently observed in tumors [45][46][47]. One possible explanation is that cancer cells may inactivate DNA damage checkpoints (such as p53) to escape Wnt dependent amplification of the DNA damage response.…”

“…Furthermore, derangement of Wnt-signaling activity contributes to impairment of stem cell function in aging tissues [15][16][17]. Our previous study revealed that Wnt-signaling activity determines sensitivity of intestinal stem and progenitor cells to DNA damage [18]. However, results from studies on the influence of levels of Wnt/β-catenin signaling on the maintenance of HSCs in the context of DNA damage seemed to be controversial [19,20].…”