The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations
Open Access
- 21 December 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (2), 466-471
- https://doi.org/10.1073/pnas.1118857109
Abstract
The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs 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+ ISCs 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 Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5+ ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.Keywords
This publication has 35 references indexed in Scilit:
- Strategies for Homeostatic Stem Cell Self-Renewal in Adult TissuesCell, 2011
- Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomesThe EMBO Journal, 2011
- Characterization of the Intestinal Cancer Stem Cell Marker CD166 in the Human and Mouse Gastrointestinal TractGastroenterology, 2010
- Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cellsProceedings of the National Academy of Sciences of the United States of America, 2010
- Paneth cells constitute the niche for Lgr5 stem cells in intestinal cryptsNature, 2010
- Intestinal Crypt Homeostasis Results from Neutral Competition between Symmetrically Dividing Lgr5 Stem CellsCell, 2010
- Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell nicheNature Medicine, 2009
- Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformationNature, 2008
- Bmi1 is expressed in vivo in intestinal stem cellsNature Genetics, 2008
- Identification of stem cells in small intestine and colon by marker gene Lgr5Nature, 2007