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

• DOI: 10.1016/j.stem.2017.06.014
• Publication Date: 2017-07-06T17:30:47Z
• Authors: Kelley S. Yan; Olivier Gevaert; Grace X.Y. Zheng; Benedict Anchang; Christopher S. Pr...; 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. Terry; Phillip Belgrader; Solongo B. Ziraldo; Tarjei S. Mikkelsen; Fengchao Wang; Richard J. von Fu...; Nicholas R. Smith; Parthasarathy Cha...; Randal May; Mary Ann S. Chrissy; Rajan Jain; Christine A. Cart...; 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
• Keywords: LGR5; Enteroendocrine cell; Cell Sorting; Stem cell marker

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.