Mex3a Marks a Slowly Dividing Subpopulation of Lgr5+ Intestinal Stem Cells.
Barriga FM., Montagni E., Mana M., Mendez-Lago M., Hernando-Momblona X., Sevillano M., Guillaumet-Adkins A., Rodriguez-Esteban G., Buczacki SJA., Gut M., Heyn H., Winton DJ., Yilmaz OH., Attolini CS-O., Gut I., Batlle E.
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.