Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration
Véronique Giroux, … , Timothy C. Wang, Anil K. Rustgi
Véronique Giroux, … , Timothy C. Wang, Anil K. Rustgi
Published May 8, 2017
Citation Information: J Clin Invest. 2017;127(6):2378-2391. https://doi.org/10.1172/JCI88941.
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Research Article Gastroenterology

Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration

Abstract

The esophageal lumen is lined by a stratified squamous epithelium comprised of proliferative basal cells that differentiate while migrating toward the luminal surface and eventually desquamate. Rapid epithelial renewal occurs, but the specific cell of origin that supports this high proliferative demand remains unknown. Herein, we have described a long-lived progenitor cell population in the mouse esophageal epithelium that is characterized by expression of keratin 15 (Krt15). Genetic in vivo lineage tracing revealed that the Krt15 promoter marks a long-lived basal cell population able to self-renew, proliferate, and generate differentiated cells, consistent with a progenitor/stem cell population. Transcriptional profiling demonstrated that Krt15+ basal cells are molecularly distinct from Krt15– basal cells. Depletion of Krt15-derived cells resulted in decreased proliferation, thereby leading to atrophy of the esophageal epithelium. Further, Krt15+ cells were radioresistant and contributed to esophageal epithelial regeneration following radiation-induced injury. These results establish the presence of a long-lived and indispensable Krt15+ progenitor cell population that provides additional perspective on esophageal epithelial biology and the widely prevalent diseases that afflict this epithelium.

Authors

Véronique Giroux, Ashley A. Lento, Mirazul Islam, Jason R. Pitarresi, Akriti Kharbanda, Kathryn E. Hamilton, Kelly A. Whelan, Apple Long, Ben Rhoades, Qiaosi Tang, Hiroshi Nakagawa, Christopher J. Lengner, Adam J. Bass, E. Paul Wileyto, Andres J. Klein-Szanto, Timothy C. Wang, Anil K. Rustgi

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Figure 2

Basal Krt15+ cells undergo division initially and migrate toward the lumen.

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Basal Krt15+ cells undergo division initially and migrate toward the lum...
(A) Krt15-CrePR1 R26mT/mG mice were injected daily with 0.5 mg RU486 for 5 consecutive days and sacrificed at listed time points. Esophageal sections were stained for GFP (Krt15+ cells) and E-cadherin (ECAD). Clonal units are marked by an asterisk. Bottom panels represent magnification of regions of interest identified by a yellow rectangle in the top panels. (B–E) Krt15-CrePR1 R26mT/mG mice were injected daily with 0.5 mg RU486 for 5 consecutive days and sacrificed 56 days after the last day of recombination. One-hundred-micrometer sections were stained with GFP (Krt15+ cells) and imaged by confocal microscopy. (B) Single-plane images 3.3 μm apart from a Z-stack. Arrows mark a GFP+ cell emerging from the basal layer. (C and D) 3D reconstruction of a clonal unit marking basal cells in blue, suprabasal cells in red, and a parabasal cell in yellow. A single basal cell not part of the clonal unit is labeled in white. Gray, DAPI. (E) Graph represents the percentage of total GFP+ cells localized in each layer (mean of 4 mice; cross sections of 4 different regions of the esophagus were analyzed for each mouse; minimum of 400 GFP+ cells were counted in each mouse; statistical significance was determined using χ2 test: χ2(15) = 969.17, P < 0.00001). (F–H) Krt15-CrePR1 R26Conf mice were injected every 12 hours with 1 mg of RU486 for 10 consecutive days and sacrificed 2 months later. (G) Whole-mount esophageal image of Krt15-CrePR1 R26Conf mice sacrificed 2 months after recombination. (H) Representative example of a monochromatic clonal unit in a transverse esophageal section. Dotted line marks the basement membrane. Scale bars: 50 μm.