Krt19+/Lgr5- Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine

Samuel Asfaha, Yoku Hayakawa, Ashlesha Muley, Sarah Stokes, Trevor A. Graham, Russell E. Ericksen, Christoph B. Westphalen, Johannes Von Burstin, Teresa L. Mastracci, Daniel L. Worthley, Chandhan Guha, Michael Quante, Anil K. Rustgi, Timothy C. Wang

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5+ cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5- stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5+ CBCs in the colon and intestine. In colorectal cancer models, Krt19+ cancer-initiating cells are also radioresistant, while Lgr5+ stem cells are radiosensitive. Moreover, Lgr5+ stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5+ stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19+ stem cells are a discrete target relevant for cancer therapy.

Original languageEnglish (US)
Pages (from-to)627-638
Number of pages12
JournalCell Stem Cell
Volume16
Issue number6
DOIs
StatePublished - Jun 4 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Asfaha, S., Hayakawa, Y., Muley, A., Stokes, S., Graham, T. A., Ericksen, R. E., Westphalen, C. B., Von Burstin, J., Mastracci, T. L., Worthley, D. L., Guha, C., Quante, M., Rustgi, A. K., & Wang, T. C. (2015). Krt19+/Lgr5- Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine. Cell Stem Cell, 16(6), 627-638. https://doi.org/10.1016/j.stem.2015.04.013