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 (TertTCE/+) 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. [Display omitted] •Tert+ cells are quiescent but conditionally repopulated upon tissue injury•Tert+ cells are indispensable for intestinal regeneration•ROS-HIFs-transactivated Wnt2b hyperactivates Wnt signaling in Tert+ cells•β-catenin induces quiescence exit of Tert+ cells Suh et al. define Tert+ cells as stem cells essential for intestinal regeneration and unveil how Tert+ intestinal stem cells escape from the quiescent state and undergo repopulation into progenitor cells upon tissue injury.