title: Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration.
abstract: The intestinal epithelium continually self-renews and can rapidly regenerate after damage. Lgr5 marks mitotically active intestinal stem cells (ISCs). Importantly, intestinal homeostasis can be maintained after depletion of Lgr5(+) cells due to the activation of Lgr5(-) reserve ISCs. The Lgr5(-) ISC populations are thought to play a similar role during intestinal regeneration following radiation-induced damage. We tested this regeneration hypothesis by combining depletion of Lgr5(+) ISCs with radiation exposure. In contrast to the negligible effect of Lgr5(+) ISC loss during homeostasis, depletion of Lgr5(+) cells during radiation-induced damage and subsequent repair caused catastrophic crypt loss and deterioration of crypt-villus architecture. Interestingly though, we found that crypts deficient for Lgr5(+) cells are competent to undergo hyperplasia upon loss of Apc. These data argue that Lgr5(-) reserve stem cells are radiosensitive and that Lgr5(+) cells are crucial for robust intestinal regeneration following radiation exposure but are dispensable for premalignant hyperproliferation.
authors: Molecular Oncology Department, Genentech, South San Francisco, CA 94080, USA.
authors: Ciara
authors: C
authors: Metcalfe
authors: Molecular Oncology Department, Genentech, South San Francisco, CA 94080, USA.
authors: Noelyn M
authors: NM
authors: Kljavin
authors: Molecular Oncology Department, Genentech, South San Francisco, CA 94080, USA.
authors: Ryan
authors: R
authors: Ybarra
authors: Molecular Oncology Department, Genentech, South San Francisco, CA 94080, USA. Electronic address: desauvage.fred@gene.com.
authors: Frederic J
authors: FJ
authors: de Sauvage
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D016264:Dextran Sulfate; D004167:Diphtheria Toxin / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D006965:Hyperplasia; D007422:Intestines / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D051379:Mice; D023421:Models, Animal; D019879:Paneth Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects / Q000528:radiation effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D004167:Diphtheria Toxin; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016264:Dextran Sulfate