Intestinal Stem Cell Function During Aging and Tumor Initiation

PROJECT SUMMARY/ABSTRACT The intestinal epithelium is a rapidly self-renewing tissue that uses distinct mechanisms for regeneration during homeostasis and injury-induced repair. Tissue regeneration is supported by heterogeneous cell types including cycling Lgr5+ intestinal stem cells (ISCs) as well as reserve stem cells set aside for times of injury. We have recently reported an essential molecular role for Wnt pathway ligands in Lgr5+ ISC maintenance and self- renewal. We have also developed novel tools for the pharmacological manipulation of the ISC niche. While adult stem cells serve to maintain and repair tissues for a lifetime, multiple studies have demonstrated that there is an age-related decline in the regenerative capacity of stem cells across multiple different tissues. Our preliminary data support diminished regenerative function in ISCs and suggest that these changes are driven by alterations in the stem cell niche that result in decreased Wnt signaling in the ISCs. We hypothesize that age- related niche alterations drive the impaired regenerative function of ISCs and these changes are reversible. Our hypothesis is evaluated by the following Specific Aims: (1) to define how the mesenchymal niche contributes to functional ISC decline in homeostatic regeneration during aging and (2) to examine ligand-level Wnt pathway manipulation in the context of colorectal tumor initiation during aging. Achievement of these Aims will provide insight into exciting new areas of ISC biology, and ultimately lead to improved strategies for tissue repair during aging.