Lgr5+ Stem Cells Are Indispensable for Radiation-Induced Intestinal Regeneration

• Simultaneous ablation of Lgr5+ cells with irradiation results in severe crypt loss
• Radiation inhibits the recovery of Lgr5+ cells after DT-induced ablation
• Depletion of Lgr5+ cells in Apc-deficient crypts does not suppress hyperplasia

SummaryThe 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.

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