Abstract 1708: Intestinal stem cells are sentinel cells for nutritional exposure

Abstract Lgr5+ CBC cells at the intestinal crypt bottom have been identified as canonical stem cells responsible for mouse intestinal mucosal homeostasis. The data establishing this are derived from mice fed standard diets that generate 25(OH)D serum levels well above the range well documented for the US population, with these higher levels reflecting that of “0” percent of the population. This is important because the Clevers group reported that expression of the vitamin D receptor (Vdr) is high in Lgr5+ cells, and decreased substantially in their immediate daughter cells, suggesting signaling through the Vdr is important for Lgr5+ CBC stem cell functions. Consistent with this, we showed that lower dietary vitamin D3 in the context of a purified western-style rodent diet, or lowering only vitamin D3 in control rodent AIN76A diet, or knockout of the vitamin D receptor specifically in Lgr5+ cells compromised the ability of Lgr5+ cells to lineage trace. Moreover, exposure to lower dietary vitamin D3 characteristic of a large segment of the US population substantially reduced the ability of introduction of a mutant Apc allele into Lgr5+ cells to generate tumors. However, the mucosa of mice exposed to these lower levels of vitamin D3 appears histologically normal and the mice are healthy. Consistent with this, Bmi1+ cells are mobilized to expand and lineage trace in mice in which lower dietary vitamin D3 established 25(OH)D levels similar to those found in the US population. Whether cells from other compartments reported to exhibit intestinal stem cell functions are also mobilized, and the relative contribution of cells from different compartments to intestinal homeostasis across the spectrum of 25(OH)D levels that characterize the human population, are under investigation. Thus, vitamin D3 is a critical factor in programming intestinal cells from different compartments to express stem cell functions. The extent and nature of this programming has been investigated by RNAseq of specific cell populations from mice fed different diets, and a number of important pathways identified linked to vitamin D exposure level. Moreover, the relationship of change in functional status for cells from different compartments (ie quiescent versus mobilized) to the mutational spectrum and load that accumulate in these cells has been analyzed by single cell exome sequencing. The sensitivity of intestinal stem cell function to vitamin D exposure suggests that the well-documented plasticity of intestinal stem cells may have evolved to permit adaptation to different environments. Moreover, this raises the questions of whether other nutrients key to maintaining intestinal homeostasis also modulate the relative contribution of different stem cell populations to intestinal homeostasis, and if the multiple cell populations capable of stem cell functions in the intestine can serve as sentinel cells for which analyses of their molecular programming are sensitive and responsive assays of nutritional exposures. Citation Format: Leonard H. Augenlicht, Wenge Li, Karina Peregrina, Michele Houston. Intestinal stem cells are sentinel cells for nutritional exposure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1708.