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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 Stem cells

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

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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 1

Krt15 marks long-lived basal cells in the mouse esophageal epithelium.

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Krt15 marks long-lived basal cells in the mouse esophageal epithelium.
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(A) Top panels: Localization of K15 in the mouse esophagus, forestomach, and tongue. Lower panels: Colocalization of K15 with p63, K13, or Ki-67 used as basal, suprabasal, and proliferative cell markers, respectively. (B and C) Krt15-CrePR1 R26mT/mG mice were injected with 0.5 mg RU486 and sacrificed 24 hours later. (B) Localization of GFP-labeled (Krt15+) cells in mouse esophageal, forestomach, and tongue epithelia. Asterisks indicate recombined cells. (C) Graph represents the percentage of total GFP cells localized in each compartment (mean of 4 mice; cross sections of 4 different regions of the esophagus were analyzed for each mouse). (D–F) Krt15-CrePR1 R26mT/mG mice were injected daily with 0.5 mg RU486 for 5 consecutive days and sacrificed at listed time points. (D) Schematic illustration of RU486 treatments and sacrifice times for the genetic lineage tracing experiments. (E) GFP (Krt15+ cells) immunofluorescence in esophageal sections of Krt15-CrePR1 R26mT/mG mice. (F) Whole-mount esophagus imaging of Krt15-CrePR1 R26mT/mG mouse sacrificed 6 months after Cre recombination. “L” indicates the lumen; dotted line marks the basement membrane. Scale bars: 50 μm.
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