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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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 5

Krt15+ basal cells have a higher clonogenic potential than Krt15– basal cells.

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Krt15+ basal cells have a higher clonogenic potential than Krt15– basal...
(A and B) 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 analyzed. Expression of genes related to esophageal epithelium stemness (A) and some tissue epithelial stem cell genes (B) was quantified by quantitative PCR. Graphs represent mean ± SEM (n = 3–7 mice for each population, *P ≤ 0.05 using 2-tailed Student’s t test). (C) 3D organoids were established from Krt15-CrePR1 R26mT/mG mice. Cre recombination was induced by RU486 treatment in vivo (left panel), in vitro when the 3D organoids were seeded (middle panel), or in vitro after 3D organoid formation (right panel). Krt15-derived cells were visualized with GFP immunofluorescence. (D and E) Krt15-CrePR1 R26mT/mG mice were injected with a single dose of RU486 and sacrificed 24 hours later. Krt15+ basal cells (CD29hiGFP+) and Krt15– basal cells (CD29hiGFP–) were sorted and seeded in Matrigel. (D) 3D organoid formation rate was assessed in 4 different mice and repeated at different passages. Graph represents mean ± SEM of a representative experiment executed in quadruplicate fashion; *P ≤ 0.05 using 2-tailed Student’s t test. (E) CD29hiGFP– and CD29hiGFP+ cell–derived 3D organoids were stained with H&E, Ki-67 (proliferative cells), and K13 (suprabasal cells). Arrow indicates rare keratin hyaline granules. Scale bars: 50 μm.