title: Mex3a Marks a Slowly Dividing Subpopulation of Lgr5+ Intestinal Stem Cells.
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.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Barriga
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Montagni
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
authors.forename: Miyeko
authors.initials: M
authors.lastname: Mana
authors.affiliation: CNAG-CRG-Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Mendez-Lago
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Hernando-Momblona
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Sevillano
authors.affiliation: CNAG-CRG-Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Amy
authors.initials: A
authors.lastname: Guillaumet-Adkins
authors.affiliation: CNAG-CRG-Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Rodriguez-Esteban
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Simon J A
authors.initials: SJA
authors.lastname: Buczacki
authors.affiliation: CNAG-CRG-Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: CNAG-CRG-Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Winton
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
authors.forename: Omer H
authors.initials: OH
authors.lastname: Yilmaz
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Camille Stephan-Otto
authors.initials: CS
authors.lastname: Attolini
authors.affiliation: CNAG-CRG-Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain. Electronic address: eduard.batlle@irbbarcelona.org.
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C493597:Lgr5 protein, mouse; D016601:RNA-Binding Proteins; D043562:Receptors, G-Protein-Coupled
keywords: Lgr5+ ISC heterogeneity; chemotherapy resistance; quiescent stem cell