title: BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.
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. Stem Cells 2016;34:1626-1636.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Vishruth K
authors.initials: VK
authors.lastname: Reddy
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Short
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Caitlyn W
authors.initials: CW
authors.lastname: Barrett
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mukul K
authors.initials: MK
authors.lastname: Mittal
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Cody E
authors.initials: CE
authors.lastname: Keating
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Thompson
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Harris
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Revetta
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Bader
authors.affiliation: Developmental Dynamics, Heart Science Centre, Imperial College London, London, U.K.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brand
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays; D017353:Gene Deletion; D006706:Homeostasis / Q000528:radiation effects; D007422:Intestines / Q000166:cytology*; D008297:Male; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000528:radiation effects; D018874:Spheroids, Cellular / Q000378:metabolism / Q000528:radiation effects; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D060449:Wnt Signaling Pathway / Q000528:radiation effects
chemical_list: C498789:Bves protein, mouse; D015815:Cell Adhesion Molecules; D009124:Muscle Proteins
keywords: Blood vessel epicardial substance; Radiation biology; Radiation enteritis; Stem cells; Wnt signaling