Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors
  • Acyltransferases / physiology*
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents, Hormonal / pharmacology
  • Bronchodilator Agents / pharmacology
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple*
  • Female
  • Homeostasis
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multidrug Resistance-Associated Proteins / metabolism
  • Myofibroblasts / cytology
  • Myofibroblasts / drug effects*
  • Myofibroblasts / metabolism
  • Propionates / pharmacology
  • Quinolines / pharmacology
  • Signal Transduction
  • Stem Cell Niche / drug effects*
  • Tamoxifen / pharmacology
  • Wnt Proteins / metabolism


  • Antibiotics, Antineoplastic
  • Antineoplastic Agents, Hormonal
  • Bronchodilator Agents
  • Membrane Proteins
  • Multidrug Resistance-Associated Proteins
  • Propionates
  • Quinolines
  • Wnt Proteins
  • Tamoxifen
  • verlukast
  • Doxorubicin
  • Acyltransferases
  • Porcn protein, mouse
  • multidrug resistance-associated protein 1