Understanding stem cell heterogeneity and niche function in intestinal regeneration after irradiation

ABSTRACT The intestinal epithelium exhibits rapid turnover mediated by intestinal stem cell (ISCs). Although Lgr5+ CBC cells have been well-accepted as the homeostatic ISC responsible for tissue regeneration, the Yan lab at Columbia University Medical Center has recently identified a putative new stem/progenitor cell located in the upper crypt “TA zone” region that is characterized by high-level expression of FGFBP1, a fibroblast growth factor carrier protein that is known to play a role in cell proliferation, differentiation, and migration. In vivo lineage tracing suggests Fgfbp1+ cells in the upper crypt give rise to Lgr5+ cells that repopulate the crypt base as well as cells that migrate in the opposite direction to replenish differentiated cells that line the villus that suggest their ISC function during homeostasis. However, the signals that regulate Fgfbp1+ cell function, their cellular role in tissue injury-repair, and our ability to harness their regenerative potential ex vivo remain completely unknown. Collaborative studies that leverage the collective expertise of the ISCC will address these gaps in our knowledge of Fgfbp1+ upper crypt cells using tissue injury models, diverse organoid platforms, and Wnt signaling niche manipulation. ISCC labs at Columbia, Cincinnati Children’s Medical Center, Stowers Institute for Medical Research, and our lab at Baylor College of Medicine (BCM) will collaboratively (1) Determine the cellular contribution of Fgfbp1+ cells in rotavirus-induced regeneration; (2) Determine the essential role of the Fzd 5 axis in Fgfbp1+ cells; and (3) Evaluate the ability of in vitro enteroid and organoid platforms to support Fgfbp1+ cells. These studies build on our ongoing studies in the parent U01 grant that are contributing to advancing the ISCC Trans-Consortium overarching goals of defining the essential niche component that contribute to intestinal epithelial homeostasis and that may play a role in epithelial regeneration following injury. These new ancillary studies complement our ongoing studies and use already established methods to evaluate the new ISC/progenitor population using new mouse models developed at Columbia University Medical Center.