Characterization of radioresistant epithelial stem cell heterogeneity in the damaged mouse intestine

Sci Rep. 2020 May 22;10(1):8308. doi: 10.1038/s41598-020-64987-1.

Abstract

The small intestine has a robust regenerative capacity, and various cell types serve as "cells-of-origin" in the epithelial regeneration process after injury. However, how much each population contributes to regeneration remains unclear. Using lineage tracing, we found that Lgr5-expressing cell derivatives contained radioresistant intestinal stem cells (ISCs) crucial for epithelial regeneration in the damaged intestine after irradiation. Single-cell qRT-PCR analysis showed that surviving Lgr5-expressing cell derivatives in the damaged intestine are remarkably heterogeneous, and that the expression levels of a YAP-target gene Sca1 were inversely correlated with their "stemness", suggesting that the YAP/Wnt signal balance in surviving crypt epithelial cells determines the cellular contribution to epithelial regeneration. Single-cell RNA sequencing of Sca1-Lgr5-derivatives revealed that expression of a tetraspanin family member CD81 correlated well with the expression of ISC- and proliferation-related genes. Consistent with these findings, organoid-forming ability was confined to the CD81hiSca1- fraction within the damaged crypt epithelial cells. Characterization of radioresistant epithelial stem cell heterogeneity in the damaged intestine may contribute to therapeutic strategies for gastrointestinal diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-1 / genetics
  • Ataxin-1 / metabolism
  • Cell Proliferation
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / cytology*
  • Mice
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Single-Cell Analysis
  • Stem Cells / cytology*
  • Stem Cells / metabolism

Substances

  • Ataxin-1
  • Atxn1 protein, mouse
  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled