Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

Kelley S. Yan, Olivier Gevaert, Grace X.Y. Zheng, Benedict Anchang, Christopher S. Probert, Kathryn A. Larkin, Paige S. Davies, Zhuan fen Cheng, John S. Kaddis, Arnold Han, Kelly Roelf, Ruben I. Calderon, Esther Cynn, Xiaoyi Hu, Komal Mandleywala, Julie Wilhelmy, Sue M. Grimes, David C. Corney, Stéphane C. Boutet, Jessica M. TerryPhillip Belgrader, Solongo B. Ziraldo, Tarjei S. Mikkelsen, Fengchao Wang, Richard J. von Furstenberg, Nicholas R. Smith, Parthasarathy Chandrakesan, Randal May, Mary Ann S. Chrissy, Rajan Jain, Christine A. Cartwright, Joyce C. Niland, Young Kwon Hong, Jill Carrington, David T. Breault, Jonathan Epstein, Courtney W. Houchen, John P. Lynch, Martin G. Martin, Sylvia K. Plevritis, Christina Curtis, Hanlee P. Ji, Linheng Li, Susan J. Henning, Melissa H. Wong, Calvin J. Kuo

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers, including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low-level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprises a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness. Multiple cell populations, represented by distinct markers including Lgr5 and Bmi1, are capable of reconstituting the intestinal epithelium. Using comparative RNA-sequencing and single-cell transcriptomics, Yan et al. define Bmi1-GFP+ and Prox1+ cells as enteroendocrine lineage cells that possess intestinal stem cell activity during homeostasis and injury-induced regeneration.

Original languageEnglish (US)
Pages (from-to)78-90.e6
JournalCell Stem Cell
Volume21
Issue number1
DOIs
StatePublished - Jul 6 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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