The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations.

The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmil and Lgr5 have been iridependently identified to mark long-lived multipotent lSCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmil and Lgr5 mark two functionallydistinct ISC5 in vivo. Lgr5 marks mitotically active lSCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmil marks quiescent lSCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1+ lSCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1+ ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmil marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5+ ISC5 and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration. [ABSTRACT FROM AUTHOR]