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

Francisco M. Barriga, Elisa Montagni, Miyeko Mana, Maria Mendez-Lago, Xavier Hernando-Momblona, Marta Sevillano, Amy Guillaumet-Adkins, Gustavo Rodriguez-Esteban, Simon J.A. Buczacki, Marta Gut, Holger Heyn, Douglas J. Winton, Omer H. Yilmaz, Camille Stephan Otto Attolini, Ivo Gut, Eduard Batlle

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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. Lgr5+ intestinal stem cells are considered to be a homogeneous and rapidly proliferating population. Barriga et al. show that the RNA binding protein Mex3a defines a subset of slowly proliferating Lgr5+ cells that contribute to all intestinal lineages with slow kinetics, are resistant to chemotherapy, and support intestinal regeneration.

Original languageEnglish (US)
Pages (from-to)801-816.e7
JournalCell Stem Cell
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Keywords

  • Lgr5+ ISC heterogeneity
  • chemotherapy resistance
  • quiescent stem cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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