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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.

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  • Authors+Show Affiliations

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Department of Biomedical Sciences, School of Veterinary Medicine, and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA.

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    Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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    Department of Pathology and Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

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    Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York, USA.

    Division of Gastroenterology, Department of Medicine, and. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    Source

    The Journal of clinical investigation 127:6 2017 Jun 01 pg 2378-2391

    MeSH

    Animals
    Cell Differentiation
    Cell Movement
    Cell Proliferation
    Cell Survival
    Esophagus
    Homeostasis
    Humans
    Keratin-15
    Mice, Inbred C57BL
    Mice, Knockout
    Mucous Membrane
    Promoter Regions, Genetic
    Radiation Injuries, Experimental
    Regeneration
    Stem Cells
    Transcriptional Activation

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28481227

    Citation

    Giroux, Véronique, et al. "Long-lived Keratin 15+ Esophageal Progenitor Cells Contribute to Homeostasis and Regeneration." The Journal of Clinical Investigation, vol. 127, no. 6, 2017, pp. 2378-2391.
    Giroux V, Lento AA, Islam M, et al. Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. J Clin Invest. 2017;127(6):2378-2391.
    Giroux, V., Lento, A. A., Islam, M., Pitarresi, J. R., Kharbanda, A., Hamilton, K. E., ... Rustgi, A. K. (2017). Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. The Journal of Clinical Investigation, 127(6), pp. 2378-2391. doi:10.1172/JCI88941.
    Giroux V, et al. Long-lived Keratin 15+ Esophageal Progenitor Cells Contribute to Homeostasis and Regeneration. J Clin Invest. 2017 Jun 1;127(6):2378-2391. PubMed PMID: 28481227.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. AU - Giroux,Véronique, AU - Lento,Ashley A, AU - Islam,Mirazul, AU - Pitarresi,Jason R, AU - Kharbanda,Akriti, AU - Hamilton,Kathryn E, AU - Whelan,Kelly A, AU - Long,Apple, AU - Rhoades,Ben, AU - Tang,Qiaosi, AU - Nakagawa,Hiroshi, AU - Lengner,Christopher J, AU - Bass,Adam J, AU - Wileyto,E Paul, AU - Klein-Szanto,Andres J, AU - Wang,Timothy C, AU - Rustgi,Anil K, Y1 - 2017/05/08/ PY - 2016/06/08/received PY - 2017/03/09/accepted PY - 2017/5/10/pubmed PY - 2017/9/28/medline PY - 2017/5/9/entrez SP - 2378 EP - 2391 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 127 IS - 6 N2 - 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. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/28481227/Long-lived_keratin_15+_esophageal_progenitor_cells_contribute_to_homeostasis_and_regeneration L2 - https://doi.org/10.1172/JCI88941 DB - PRIME DP - Unbound Medicine ER -