Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration
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
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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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 6

Depletion of Krt15+ cells leads to reduced proliferation and epithelial atrophy.

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Depletion of Krt15+ cells leads to reduced proliferation and epithelial ...
(A–F) Krt15-CrePR1 R26iDTR and control (R26iDTR) mice were injected daily with 0.5 mg RU486 for 5 consecutive days prior to diphtheria toxin (DT) injection to deplete Krt15-derived cells. Mice were sacrificed 12 days after DT administration or sooner in case of extensive weight loss. (B) H&E of the esophagi of Krt15-CrePR1 R26iDTR mice and age-matched R26iDTR control mice. Red lines delineate epithelial thickness. (C) Epithelial thickness was measured at 4 representative spots of 4 different cross-sectional regions of each esophagus (n = 5 mice per group). Graph represents mean ± SEM; *P ≤ 0.05 using 2-tailed Student’s t test. (D–F) Krt15-CrePR1 R26iDTR and control R26iDTR mice were injected with BrdU 1.5 hours before sacrifice, and esophageal sections were stained for Ki-67 and BrdU. The percentage of Ki-67+ (E) and BrdU+ (F) basal cells was determined. Graphs represent mean ± SEM (n = 5 mice per group, and a minimum of 500 basal cells was counted; *P ≤ 0.05 using 2-tailed Student’s t test). Scale bars: 50 μm.