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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.

SUBMITTER: Reddy VK

PROVIDER: S-EPMC4893006 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.

Reddy Vishruth K VK Short Sarah P SP Short Sarah P SP Barrett Caitlyn W CW Mittal Mukul K MK Keating Cody E CE Thompson Joshua J JJ Harris Elizabeth I EI Revetta Frank F Bader David M DM Brand Thomas T Washington M Kay MK Williams Christopher S CS

Stem cells (Dayton, Ohio) 20160315 6

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 radiat ...[more]

PMID: 26891025

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Project description:Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that ?-arrestin-2 (?arr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. ?Arr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr5(+) (leucine-rich repeat-containing G-protein-coupled receptor 5-positive) stem cell apoptosis, promoted crypt proliferation and reproduction, and protracted survival following lethal doses of radiation. Radioprotection in the ICPS cells isolated from ?arr2-deficient mice depended on prolonged nuclear factor-?B (NF-?B) activation via direct interaction of ?arr2 with I?B? and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, ?arr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, ?arr2 knockdown also provided significant radioresistance by manipulating NF-?B/PUMA signaling in Lgr5(+) cells in vitro. Collectively, these observations show that targeting the ?arr2/NF-?B/PUMA novel pathway is a potential radiomitigator for limiting the damaging effect of radiotherapy on the gastrointestinal system. Significance statement: acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiotherapy. The issue of whether the critical factor for the initiation of radiation-induced intestinal injury is intestinal stem cell apoptosis or endothelial cell apoptosis remains unresolved. ?Arrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that ?-arrestin-2 (?arr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, ?arr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-?B activation and subsequent suppression of PUMA induction. Our results suggest that ICPS cell apoptosis is the factor involved in the initiation and development of radiation-induced gastrointestinal syndrome. ?Arr2 is a potential target for lessening radiation-induced ICPS cell apoptosis.

Dataset Information

BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.

Publications

BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.

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