title: The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations.
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.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kelley S
authors.initials: KS
authors.lastname: Yan
authors.forename: Luis A
authors.initials: LA
authors.lastname: Chia
authors.forename: Xingnan
authors.initials: X
authors.lastname: Li
authors.forename: Akifumi
authors.initials: A
authors.lastname: Ootani
authors.forename: James
authors.initials: J
authors.lastname: Su
authors.forename: Josephine Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Nan
authors.initials: N
authors.lastname: Su
authors.forename: Yuling
authors.initials: Y
authors.lastname: Luo
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Heilshorn
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Amieva
authors.forename: Eugenio
authors.initials: E
authors.lastname: Sangiorgi
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D015415:Biomarkers / Q000378:metabolism*; D005434:Flow Cytometry; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology*; D008164:Luminescent Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013629:Tamoxifen; D014916:Whole-Body Irradiation
chemical_list: D001426:Bacterial Proteins; D015415:Biomarkers; C489421:Bmi1 protein, mouse; C493597:Lgr5 protein, mouse; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; C054562:yellow fluorescent protein, Bacteria; D013629:Tamoxifen; D063150:Polycomb Repressive Complex 1