Characterization of Lrig1+ colonic stem/progenitor cells and their transformative capacity

Abstract

The intestinal epithelium is a continuously renewing tissue. This rapid renewal is fueled by stem cells that reside in the base of the crypts of Lieberkühn, the functional unit of the intestinal epithelium. The identity of intestinal stem cells has been the subject of over fifty years of ongoing investigation. Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) marks a population of intestinal stem cells, but the identity of Lrig1+ cells has remained controversial due to discrepant reports of Lrig1 expression in the crypt base. We characterized two Lrig1+ populations in the colonic epithelium using two anti-Lrig1 antibodies and a new Lrig1 reporter mouse. We determined that these two populations could be distinguished by reporter expression, Lgr5 expression, and likely the glycosylation status of Lrig1. Since stem cells are widely considered to be tumor-initiating cells in colorectal cancer, we developed new mouse models of colonic neoplasia: Lrig1CreERT2/+;Apcfl/fl and Lrig1CreERT2/+;Apcfl/fl;KrasLSL-G12D/+. We found that Apc loss resulted in high-grade tumors; expression of mutant Kras expression did not significantly affect histological grade of tumors, but may contribute to increased invasion.