Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation

Winnie Y. Zou, Sarah E. Blutt, Xi Lei Zeng, Min Shan Chen, Yuan Hung Lo, David Castillo-Azofeifa, Ophir D. Klein, Noah F. Shroyer, Mark Donowitz, Mary K. Estes

Research output: Contribution to journalArticle


Intestinal stem cells (ISCs) maintain and repair the intestinal epithelium. While regeneration after ISC-targeted damage is increasingly understood, injury-repair mechanisms that direct regeneration following injuries to differentiated cells remain uncharacterized. The enteric pathogen, rotavirus, infects and damages differentiated cells while sparing all ISC populations, thus allowing the unique examination of the response of intact ISC compartments during injury-repair. Upon rotavirus infection in mice, ISC compartments robustly expand and proliferating cells rapidly migrate. Infection results specifically in stimulation of the active crypt-based columnar ISCs, but not alternative reserve ISC populations, as is observed after ISC-targeted damage. Conditional ablation of epithelial WNT secretion diminishes crypt expansion and ISC activation, demonstrating a previously unknown function of epithelial-secreted WNT during injury-repair. These findings indicate a hierarchical preference of crypt-based columnar cells (CBCs) over other potential ISC populations during epithelial restitution and the importance of epithelial-derived signals in regulating ISC behavior. Using rotavirus infection as an intestinal epithelial injury model, Zou et al. demonstrate that crypt-based columnar cells are the predominant cell type responding to epithelial villus injury, and WNT ligands secreted from the intestinal epithelium are essential for this regenerative process.

Original languageEnglish (US)
Pages (from-to)1003-1015
Number of pages13
JournalCell Reports
Issue number4
StatePublished - Jan 23 2018



  • epithelial WNT
  • intestinal stem cell
  • ISC
  • regeneration
  • rotavirus
  • RV

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zou, W. Y., Blutt, S. E., Zeng, X. L., Chen, M. S., Lo, Y. H., Castillo-Azofeifa, D., Klein, O. D., Shroyer, N. F., Donowitz, M., & Estes, M. K. (2018). Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation. Cell Reports, 22(4), 1003-1015. https://doi.org/10.1016/j.celrep.2017.12.093