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 beta-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.