Abstract
Abstract Background: Intestinal stem cells regulate the emergence of different cell lineages across the crypt-villus axis and orchestrate cellular renewal and replenishment following injury (e.g. radiation). Two major ISC have been identified to date: a rapidly cycling crypt base columnar (CBC) stem cell and a more quiescent reserve stem cell located at the +4 position above the crypt base. CBCs marked by the Wnt target gene Lgr5 are dispensable for homeostasis and are quantitatively ablated by radiation injury. In contrast, quiescent ISCs are indispensable for homeostasis, regenerate CBCs, and are radioresistant. Keratins (Krt) are intermediate filaments required for architectural and mechanical support, but also contribute to cell migration and intracellular signaling. Interestingly, Krt15 has been characterized as a stem cell marker in the hair follicle. Here we described a radio-resistant Krt15+ stem cell population in the small intestine and demonstrate that cells within this population are capable of tumor initiation. Methods: Krt15-CrePR1 mice were crossed with Rosa26 reporter mice to perform lineage-tracing experiments in the mouse small intestine. High-dose radiation was used to investigate the role of Krt15 in tissue regeneration. Finally, Krt15-CrePR1 mice were crossed with Apcfl/fl mice to characterize the tumor-initiating properties of Krt15+ cells. Results: We observed that Krt15 marks a subpopulation of long-lived small intestinal crypt cells that are able to give rise to all differentiated lineages supporting their self-renewing and multipotent capacities. Interestingly, we observed that Krt15+ cells are able to form 3D organoids when seeded in Matrigel as a single cell suspension. Irradiation of Krt15-CrePR1;R26mTomato/mGFP mice with 12 Gy revealed that Krt15+ cells are radio-resistant and participate in tissue regeneration. Interestingly, Krt15 deficiency impairs tissue regeneration following high-dose radiation. Indeed, irradiated Krt15-/- mice display reduced crypt regeneration, crypt length, microcolonies and BrdU incorporation when compared to irradiated Krt15+/+ mice. Finally, we induced Apc loss in Krt15+ cells and observed formation of adenomas as well as adenocarcinomas in all Krt15-CrePR1;Apcfl/fl mice. Metastases were detected in some Krt15-CrePR1;Apcfl/fl mice. Conclusion: We have identified a long-lived Krt15+ subpopulation of intestinal crypt cells displaying stem cell-like properties that are radio-resistant and tumor initiating. This new stem cell population may open new avenues for therapeutic targeting in colon cancer. Citation Format: Veronique Giroux, Julien Stephan, Kathryn E. Hamilton, Priya Chatterjee, Sarah Andres, Andres J. Klein-Szanto, Christopher J. Lengner, Anil K. Rustgi. Keratin15 (Krt15) + are radio resistant and tumor-initiating cells in the mouse small intestine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5022. doi:10.1158/1538-7445.AM2017-5022
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