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

Cell Rep. 2017 Nov 28;21(9):2571-2584. doi: 10.1016/j.celrep.2017.10.118.

Abstract

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.

Keywords: ROS-HIFs-Wnt2b; Tert; Wnt/β-catenin; intestinal regeneration; intestinal stem cells; radiation.

MeSH terms

  • Animals
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism*
  • Intestines / physiology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Regeneration / genetics
  • Regeneration / physiology
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / genetics
  • Wnt Signaling Pathway / physiology
  • beta Catenin / metabolism*

Substances

  • Wnt Proteins
  • beta Catenin
  • Telomerase