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

Author(s)
Barriga, Francisco M.; Montagni, Elisa; Mendez-Lago, Maria; Hernando-Momblona, Xavier; Sevillano, Marta; Guillaumet-Adkins, Amy; Rodriguez-Esteban, Gustavo; Buczacki, Simon J.A.; Gut, Marta; Heyn, Holger; Winton, Douglas J.; Attolini, Camille Stephan-Otto; Gut, Ivo; Batlle, Eduard; Mana, Miyeko; Yilmaz, Omer; ... Show more Show less
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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. Keywords: Lgr5+ ISC heterogeneity; quiescent stem cell; chemotherapy resistance
Date issued
2017-03
URI
http://hdl.handle.net/1721.1/117056
Department
David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology
Journal
Cell Stem Cell
Publisher
Elsevier
Citation
Barriga, Francisco M. et al. “Mex3a Marks a Slowly Dividing Subpopulation of Lgr5+ Intestinal Stem Cells.” Cell Stem Cell 20, 6 (June 2017): 801–816 © 2017 Elsevier Inc
Version: Author's final manuscript
ISSN
1934-5909

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