Blood Vessel Epicardial Substance (BVES/Popdc1) is a junctional-associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial-to-mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves–/– mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5 compared to wildtype (WT) mice. Intercross with Lgr5-EGFP reporter mice confirmed expansion of the stem cell compartment in Bves –/– mice. To examine stem cell function after BVES deletion, we employed ex vivo 3D-enteroid cultures. Bves–/– enteroids demonstrated increased stemness compared to WT, when examining parameters such as plating efficiency, stem spheroid formation, and retention of peripheral cystic structures. Furthermore, we observed increased proliferation, expression of crypt-base columnar “CBC” and “+4” stem cell markers, and amplified Wnt signaling in the Bves–/– enteroids. Bves expression was downregulated after radiation in WT mice. Moreover, after radiation, Bves–/– mice demonstrated significantly greater crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves–/– mice also demonstrated elevation in Lgr5 and Ascl2 expression, and putative damage-responsive stem cell populations marked by Bmi1 and TERT. Therefore, BVES is a key regulator of intestinal stem cell programs and mucosal homeostasis.
|Advisor:||Williams, Christopher S.|
|Commitee:||Bader, David M., Fingleton, Barbara, Washington, M. Kay, Williams, Christopher S., Wilson, Keith T.|
|School Location:||United States -- Tennessee|
|Source:||DAI-B 80/06(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Health sciences, Oncology|
|Keywords:||Cancer biology, Intestinal biology, Oncology, Radiation biology, Radiation enteritis, Stem cells|
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