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 7

Krt15+ cells are radioresistant to high-dose radiation.

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Krt15+ cells are radioresistant to high-dose radiation. (A–D) Krt15-Cre...
(A–D) Krt15-CrePR1 R26mT/mG mice were injected daily with 0.5 mg RU486 for 5 consecutive days. Fifty percent of mice were subjected to 12 Gy whole-body irradiation on the following day, and sacrificed 2 or 5 days after radiation. (B) Krt15-derived cells were visualized by GFP immunofluorescence in the esophagi of Krt15-CrePR1 R26mT/mG mice that were irradiated or not irradiated (NI). (C and D) p-H2AX and GFP (Krt15-derived cells) immunofluorescence was performed of esophagi harvested from the mice sacrificed 2 days after irradiation. (D) Percentage of p-H2AX+ staining in Krt15– and Krt15+ basal cells was quantified. Graph represents mean ± SEM (n = 3 mice; cross sections of 4 different regions of the esophagus were analyzed for each mouse); *P ≤ 0.05 using 2-tailed Student’s t test. (E and F) Krt15-CrePR1 R26mT/mG mice were subjected to 12 Gy whole-body irradiation and then injected every 12 hours with RU486 until sacrifice 48 hours after irradiation. (F) Krt15-derived cells were visualized by GFP immunofluorescence in the esophagi of Krt15-CrePR1 R26mT/mG mice. (G) Krt15-CrePR1 R26mT/mG mice were injected once with 0.5 mg RU486 and sacrificed 24 hours later. Krt15+ basal cells (CD29hiGFP+) and Krt15– basal cells (CD29hiGFP–) were sorted and subjected to RNA-Seq. GSEA was performed in Krt15+ and Krt15– basal cells. Plot of DNA integrity checkpoint gene set enriched in Krt15+ basal cells (false discovery rate < 0.25 and P < 0.05). “L” indicates the lumen; dotted line marks the basement membrane. Scale bars: 50 μm.