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

Publication date: 6 July 2017
Source:Cell Stem Cell, Volume 21, Issue 1
Author(s): 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. Terry, Phillip 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
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.

Graphical abstract

Teaser

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.


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