Quiescence Exit of Tert⁺ Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration

Fine control of stem cell maintenance and activation is crucial for tissue homeostasis and regeneration. However, the mechanism of quiescence exit of Tert⁺ intestinal stem cells (ISCs) remains unknown. Employing a Tert knockin (Tert^TCE/+) mouse model, we found that Tert⁺ cells are long-term label-retaining self-renewing cells, which are partially distinguished from the previously identified +4 ISCs. Tert⁺ cells become mitotic upon irradiation (IR) injury. Conditional ablation of Tert⁺ cells impairs IR-induced intestinal regeneration but not intestinal homeostasis. Upon IR injury, Wnt signaling is specifically activated in Tert⁺ cells via the ROS-HIFs-transactivated Wnt2b signaling axis. Importantly, conditional knockout of β-catenin/Ctnnb1 in Tert⁺ cells undermines IR-induced quiescence exit of Tert⁺ cells, which subsequently impedes intestinal regeneration. Our results that Wnt-signaling-induced activation of Tert⁺ ISCs is indispensable for intestinal regeneration unveil the underlying mechanism for how Tert⁺ stem cells undergo quiescence exit upon tissue injury.