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

摘要

Summary 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.