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Cell Stem Cell. 2017 Jul 6;21(1):78-90.e6. doi: 10.1016/j.stem.2017.06.014.

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

Author information

1
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Columbia Center for Human Development, Columbia Stem Cell Initiative, Department of Medicine, Division of Digestive and Liver Diseases, Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
2
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
10x Genomics, Inc., Pleasanton, CA 94566, USA.
4
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Oregon Health & Science University, Department of Cell, Developmental and Cancer Biology, Portland, OR 97239, USA.
7
Department of Diabetes and Cancer Discovery Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
8
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Columbia Center for Translational Immunology, Department of Medicine, Division of Digestive and Liver Diseases, Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
9
Columbia Center for Human Development, Columbia Stem Cell Initiative, Department of Medicine, Division of Digestive and Liver Diseases, Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
10
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
11
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
12
Department of Internal Medicine, Division of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
13
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
14
Departments of Surgery and of Biochemistry & Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
15
National Institutes of Health, Division of Digestive Diseases and Nutrition, NIDDK, Bethesda, MD 20892, USA.
16
Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA.
17
Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
18
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
19
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: cjkuo@stanford.edu.

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.

PMID:
28686870
PMCID:
PMC5642297
DOI:
10.1016/j.stem.2017.06.014
[Indexed for MEDLINE]
Free PMC Article

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