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Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating

2018; Elsevier BV; Volume: 10; Issue: 6 Linguagem: Inglês

10.1016/j.stemcr.2018.04.022

2213-6711

Véronique Giroux, Julien Stephan, Priya Chatterji, Ben Rhoades, E. Paul Wileyto, Andres J. Klein–Szanto, Christopher J. Lengner, Kathryn E. Hamilton, Anil K. Rustgi,

Wnt/β-catenin signaling in development and cancer

Two principal stem cell pools orchestrate the rapid cell turnover in the intestinal epithelium. Rapidly cycling Lgr5+ stem cells are intercalated between the Paneth cells at the crypt base (CBCs) and injury-resistant reserve stem cells reside above the crypt base. The intermediate filament Keratin 15 (Krt15) marks either stem cells or long-lived progenitor cells that contribute to tissue repair in the hair follicle or the esophageal epithelium. Herein, we demonstrate that Krt15 labels long-lived and multipotent cells in the small intestinal crypt by lineage tracing. Krt15+ crypt cells display self-renewal potential in vivo and in 3D organoid cultures. Krt15+ crypt cells are resistant to high-dose radiation and contribute to epithelial regeneration following injury. Notably, loss of the tumor suppressor Apc in Krt15+ cells leads to adenoma and adenocarcinoma formation. These results indicate that Krt15 marks long-lived, multipotent, and injury-resistant crypt cells that may function as a cell of origin in intestinal cancer.