Characterizing the role of NR4A1 in the regulation of intestinal smooth muscle cell phenotype and function
Date
2021-04-06
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Intestinal fibrosis and stricture formation are common complications of Crohn’s disease (CD). Recently, smooth muscle hypertrophy and hyperplasia have gained greater recognition as a driver of stricture formation, rather than an increase in fibrosis alone. Despite advances in treatment of CD, current therapies do little to prevent or reverse strictures. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor (NR) that is anti-fibrotic in non-intestinal systems and exhibits anti-proliferative effects in smooth muscle cells (SMCs). NR4A1 gene variants have been associated with increased risk of IBD, however, mechanisms regulating NR4A1 expression and its role in intestinal SMC function have not been investigated. We therefore hypothesized that presence and activation of NR4A1 regulates cell proliferation and metabolism by modulating intestinal SMC phenotype. Primary intestinal SMCs isolated from Nr4a1+/+ and Nr4a1-/- mice and a commercially sourced human primary intestinal SMC line were used as in vitro models. We employed the chronic model of dextran sulfate sodium (DSS) and the SAMP1/YitFc model of spontaneous ileitis as in vivo models. In alignment with our hypothesis, NR4A1 presence and exposure to identified agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP), regulated key cellular mechanisms involved in excessive smooth muscle hypertrophy and hyperplasia. NR4A1 expression was significantly induced in human colonic SMCs by platelet-derived growth factor (PDGF)-BB suggesting a potential negative feedback mechanism to control mitogen-induced SMC proliferation. Taken together, in this study, NR4A1 is shown to be a vital brake in intestinal SMC phenotypic modulation by limiting excessive proliferation and other associated characteristics that could contribute to pathogenic tissue remodelling observed in fibrostenotic CD.
Description
Keywords
Nuclear receptor, Inflammatory bowel disease, Smooth muscle
Citation
Szczepanski, H. E. (2021). Characterizing the role of NR4A1 in the regulation of intestinal smooth muscle cell phenotype and function (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.