Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids.

Lee-Jung Tak,Yoojin Seo,Ji Won Yang,Eun-Joo An,Hyung-Sik Kim,Tae-Yoon Kim,Min Jung Lee,Won-Kook Ham,Gaurav Agrahari,Hae-Young Kim,Chul Hwan Bang

doi:10.3390/ijms22126431

Abstract

Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.

Highlights

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a complex multifactorial disease that affects the gastrointestinal tract with chronic and excessive inflammation
We have previously shown its therapeutic potential in many inflammatory diseases; since the half-life of Superoxide dismutase 3 (SOD3) is short, it is limited in its use as a therapeutic substance by itself
It has been reported that the use of SOD3-mesenchymal stem cells (MSCs) infected with Lenti-SOD3 in MSCs may play an effective anti-inflammatory role compared to the use of SOD3 or MSCs alone [16,25]

Summary

Introduction

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a complex multifactorial disease that affects the gastrointestinal tract with chronic and excessive inflammation. Mitogenactivated protein kinases (MAPK) are Ser/Thr protein kinases that respond to extracellular stimuli such as growth factors and stress, and regulate various cellular activities including gene expression, mitosis, differentiation, and apoptosis. The activation of MAPK signaling leads to elevated production and secretion of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α in IBD [3]. Oxidative stress derived from excessive ROS production can cause lipid peroxidation, intestinal mucosal barrier damage, bacterial translocation, and an inflammatory response. In UC, one type of IBD, oxidative stress has been shown to play a critical role in its pathogenesis and malignant progression to colorectal cancer (CRC) [4]. Evidence of ROS-induced epithelial damage during IBD progression have been suggested [5]

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