BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation. (15th March 2016)

• Record Type: Journal Article
• Authors: Reddy, Vishruth K.; Short, Sarah P.; Barrett, Caitlyn W.; Mittal, Mukul K.; Keating, Cody E.; Thompson, Joshua J.; Harris, Elizabeth I.; Revetta, Frank; Bader, David M.; Brand, Thomas; Washington, M. Kay; Williams, Christopher S.
• Is Part Of: Stem cells. Volume 34:Number 6(2016:Jun.)
• Page Start: 1626
• Page End: 1636
• Publication Date: 2016-03-15
• Subjects: Blood vessel epicardial substance -- Stem cells -- Radiation enteritis -- Wnt signaling -- Radiation biology; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2307
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: 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 wild-type (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 used 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, amplified Wnt signaling, and responsiveness to Wnt activation in the Bves –/– enteroids. Bves expression was downregulated after radiation in WT mice. Moreover, after radiation, Bves –/– mice demonstrated significantly greater SI crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves –/– mice also demonstrated elevations 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.