Mex3a Marks a Slowly Dividing Subpopulation of Lgr5+ Intestinal Stem Cells

Cell Stem Cell. 2017 Jun 1;20(6):801-816.e7. doi: 10.1016/j.stem.2017.02.007. Epub 2017 Mar 9.

Abstract

Highly proliferative Lgr5+ stem cells maintain the intestinal epithelium and are thought to be largely homogeneous. Although quiescent intestinal stem cell (ISC) populations have been described, the identity and features of such a population remain controversial. Here we report unanticipated heterogeneity within the Lgr5+ ISC pool. We found that expression of the RNA-binding protein Mex3a labels a slowly cycling subpopulation of Lgr5+ ISCs that contribute to all intestinal lineages with distinct kinetics. Single-cell transcriptome profiling revealed that Lgr5+ cells adopt two discrete states, one of which is defined by a Mex3a expression program and relatively low levels of proliferation genes. During homeostasis, Mex3a+ cells continually shift into the rapidly dividing, self-renewing ISC pool. Chemotherapy and radiation preferentially target rapidly dividing Lgr5+ cells but spare the Mex3a-high/Lgr5+ population, helping to promote regeneration of the intestinal epithelium following toxic insults. Thus, Mex3a defines a reserve-like ISC population within the Lgr5+ compartment.

Keywords: Lgr5+ ISC heterogeneity; chemotherapy resistance; quiescent stem cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / physiology*
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism*
  • Mice
  • Mice, Transgenic
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism*

Substances

  • Lgr5 protein, mouse
  • RNA-Binding Proteins
  • Receptors, G-Protein-Coupled