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Stem Cell Reports. 2018 Jun 5;10(6):1947-1958. doi: 10.1016/j.stemcr.2018.04.022. Epub 2018 May 24.

Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating.

Author information

1
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, 951 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Pathology and Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
4
Department of Biomedical Sciences, School of Veterinary Medicine, Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, 951 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
6
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, 951 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: anil2@mail.med.upenn.edu.

Abstract

Two principal stem cell pools orchestrate the rapid cell turnover in the intestinal epithelium. Rapidly cycling Lgr5+ stem cells are intercalated between the Paneth cells at the crypt base (CBCs) and injury-resistant reserve stem cells reside above the crypt base. The intermediate filament Keratin 15 (Krt15) marks either stem cells or long-lived progenitor cells that contribute to tissue repair in the hair follicle or the esophageal epithelium. Herein, we demonstrate that Krt15 labels long-lived and multipotent cells in the small intestinal crypt by lineage tracing. Krt15+ crypt cells display self-renewal potential in vivo and in 3D organoid cultures. Krt15+ crypt cells are resistant to high-dose radiation and contribute to epithelial regeneration following injury. Notably, loss of the tumor suppressor Apc in Krt15+ cells leads to adenoma and adenocarcinoma formation. These results indicate that Krt15 marks long-lived, multipotent, and injury-resistant crypt cells that may function as a cell of origin in intestinal cancer.

KEYWORDS:

intestinal crypts; keratin 15; radiation injury; stem cells; tumor

PMID:
29805107
PMCID:
PMC5993649
DOI:
10.1016/j.stemcr.2018.04.022
[Indexed for MEDLINE]
Free PMC Article

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