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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.

Original publication

DOI

10.1016/j.stem.2017.02.007

Type

Journal article

Journal

Cell Stem Cell

Publication Date

01/06/2017

Volume

20

Pages

801 - 816.e7

Keywords

Lgr5+ ISC heterogeneity, chemotherapy resistance, quiescent stem cell, Animals, Cell Proliferation, Intestinal Mucosa, Mice, Mice, Transgenic, RNA-Binding Proteins, Receptors, G-Protein-Coupled, Stem Cells