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Dev Cell. 2018 Sep 24;46(6):681-695.e5. doi: 10.1016/j.devcel.2018.07.023. Epub 2018 Aug 23.

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche.

Author information

1
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
2
University of Oslo (UiO) & Oslo University Hospital (OUS), Department of Pathology, Translational Neurodegeneration Research and Neuropathology Lab, Oslo 0316, Norway; University of Lübeck (UzL), LIED, Lübeck 23562, Germany; Leibniz-Institute of Plant Biochemistry (IPB), Halle 06120, Germany.
3
Institute of Chemical and Engineering Sciences (ICES), Agency for Science Technology and Research (A(∗)STAR), Singapore 138665, Singapore.
4
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore. Electronic address: babita.madan@duke-nus.edu.sg.
5
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27703, USA.

Abstract

The gut absorbs dietary nutrients and provides a barrier to xenobiotics and microbiome metabolites. To cope with toxin exposures, the intestinal epithelium is one of the most rapidly proliferating tissues in the body. The stem cell niche supplies essential signaling factors including Wnt proteins secreted by subepithelial myofibroblasts. Unexpectedly, therapeutically effective doses of orally administered PORCN inhibitors that block all Wnt secretion do not affect intestinal homeostasis. We find that intestinal myofibroblasts are intrinsically resistant to multiple xenobiotics, including PORCN inhibitors and the anthracycline antibiotic doxorubicin. These myofibroblasts have high expression of a subset of drug transporters; knockout of Mrp1/Abcc1 enhances drug sensitivity. Tamoxifen administration to Rosa26CreERT2;mT/mG mice visually highlights the drug-resistant intestinal stromal compartment and identifies small populations of drug-resistant cells in lung, kidney, and pancreatic islets. Xenobiotic resistance of the Wnt-producing myofibroblasts can protect the intestinal stem cell niche in the face of an unpredictable environment.

KEYWORDS:

ABCC1; PORCN inhibitors; Wnt inhibitors; Wnt signaling; drug efflux pumps; drug resistance mechanisms; intestinal stem cell niche

Comment in

PMID:
30146480
DOI:
10.1016/j.devcel.2018.07.023
[Indexed for MEDLINE]
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