The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian tissues. Genetic inducible fate mapping studies have identified two principal epithelial stem cell pools in this tissue. One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the crypt base1. The other pool consists of Bmi1-expressing cells that largely reside above the crypt base2. However, the relative functions of these two pools and their interrelationship are not understood. Here we specifically ablated Lgr5-expressing cells in mice using a human diphtheria toxin receptor (DTR) gene knocked into the Lgr5 locus. We found that complete loss of the Lgr5-expressing cells did not perturb homeostasis of the epithelium, indicating that other cell types can compensate for the elimination of this population. After ablation of Lgr5-expressing cells, progeny production by Bmi1-expressing cells increased, indicating that Bmi1-expressing stem cells compensate for the loss of Lgr5-expressing cells. Indeed, lineage tracing showed that Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a hierarchy of stem cells in the intestinal epithelium. Our results demonstrate that Lgr5-expressing cells are dispensable for normal intestinal homeostasis, and that in the absence of these cells, Bmi1-expressing cells can serve as an alternative stem cell pool. These data provide the first experimental evidence for the interrelationship between these populations. The Bmi1-expressing stem cells may represent both a reserve stem cell pool in case of injury to the small intestine epithelium and a source for replenishment of the Lgr5-expressing cells under non-pathological conditions.
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We gratefully acknowledge efforts by all the members of the Genentech mouse facility, in particular R. Ybarra and G. Morrow. We are grateful to N. Strauli, D.-K. Tran and A. Rathnayake for assistance with mouse breeding. We thank M. Roose-Girma, X. Rairdan and the members of the embryonic stem cell and microinjection groups for embryonic stem cell work and transgenic line generation and members of the F.J.d.S. laboratory for discussions and ideas. This work was funded in part by the National Institutes of Health through the NIH Director’s New Innovator Award Program, 1-DP2-OD007191 and by R01-DE021420, both to O.D.K.
The file contains Supplementary Figures 1-8 with legends.
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Journal of Immunology Research (2019)