Keratin 15+ progenitors maintain rapid renewal and regeneration in esophageal epithelium

The esophageal epithelium experiences a high rate of cellular renewal that supports rapid tissue regeneration in response to injury. The stratified organization of the epithelium restricts proliferative cells to the basal layer, and these cells must migrate toward the lumen as they differentiate. This week in the JCI, a study led by Anil Rustgi at the University of Pennsylvania identifies keratin 15 as a marker for a subpopulation of proliferative stem cells in the esophagus that are indispensible for maintaining homeostasis as well as regenerating tissue following injury.

Giroux et al. performed in vivo lineage tracing studies to determine that expression of the keratin 15 promoter distinguishes a distinct basal stem cell population that is capable of self-renewal, proliferation, and differentiation into squamous-lineage cells. In mice, depletion of this keratin 15-expressing population impaired esophageal tissue renewal after injury. These findings indicate that keratin 15+ progenitors give rise to a population of squamous epithelial cells that are critical to recovery from injury and disease.

The accompanying images depict the basal epithelium of the esophageal lumen (dark purple) in wild-type (left) and keratin 15-deficient mice (right) following radiation-induced injury. Although wild-type mice displayed normal morphology 15 days after injury, tissue regeneration remained incomplete in mice lacking keratin 15+ cells. Image credit: Véronique Giroux

Published May 8, 2017, by Elyse Dankoski

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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

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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