IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

Abstract

Background. Ischemia reperfusion injury (IRI) is the major cause of intestinal damage in clinic. Although either mesenchymal stromal cells (MSCs) or interleukin 37 (IL-37) shows some beneficial roles to ameliorate IRI, their effects are limited. In this study, the preventative effects of IL-37 gene-modified MSCs (IL-37-MSCs) on intestinal IRI are investigated. Methods. Intestinal IRI model was established by occluding the superior mesenteric artery for 30 minutes and then reperfused for 72 hours in rats. Forty adult male Sprague-Dawley rats were randomly divided into the sham control, IL-37-MSC-treated, MSC-treated, recombinant IL-37- (rIL-37-) treated, and untreated groups. Intestinal damage was assessed by H&E staining. The levels of gut barrier function factors (diamine oxidase and D-Lactate) and inflammation cytokine IL-1β were assayed using ELISA. The synthesis of tissue damage-related NLRP3 inflammasome and downstream cascade reactions including cleaved caspase-1, IL-1β, and IL-18 was detected by western blot. The mRNA levels of proinflammatory mediators IL-6 and TNF-α, which are downstream of IL-1β and IL-18, were determined by qPCR. Data were analyzed by one-way analysis of variance (ANOVA) after the normality test and followed by post hoc analysis with the least significant difference (LSD) test. Results. IL-37-MSCs were able to migrate to the damaged tissue and significantly inhibit intestinal IRI. As compared with MSCs or the rIL-37 monotherapy group, IL-37-MSC treatment both improved gut barrier function and decreased local and systemic inflammation cytokine IL-1β level in IRI rats. In addition, tissue damage-related NLRP3 and downstream targets (cleaved caspase-1, IL-1β, and IL-18) were significantly decreased in IRI rats treated with IL-37-MSCs. Furthermore, IL-1β- and IL-18-related proinflammatory mediator IL-6 and TNF-α mRNA expressions were all significantly decreased in IRI rats treated with IL-37-MSCs. Conclusion. The results suggest that IL-37 gene modification significantly enhances the protective effects of MSCs against intestinal IRI. In addition, NLRP3-related signaling pathways could be associated with IL-37-MSC-mediated protection.

Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke

“…There were also studies on MSC-derived miRNAs or circular RNAs (circRNAs) downregulating pyroptotic components in hypoxia/reoxygenation renal epithelial cells or ischemic muscle (Yuan et al, 2017;Yan et al, 2020). Besides, Kong and his group transplanted IL-37 gene-modified MSCs into rats model of intestinal ischemia-reperfusion injury and found that the expression of NLRP3 and downstream targets (cleaved caspase-1, IL-1β, and IL-18) were observably lessened (Kong et al, 2020). Overall, the underlying mechanism regarding multiple molecular pathways involved in the role of MSCs and secretome in other diseases are expected to further elucidate in ischemic stroke.…”

The efficacy of bone marrow mesenchymal stem cells on rat intestinal immune-function injured by ischemia/reperfusion

“…In the event of I/R, intestinal immune barrier dysfunction will lead to cytokine release, intestinal inflammatory injury and bacterial invasion and migration [ 6 ], resulting in serious body damage. Many studies have demonstrated successful application of BMSCs in reducing intestinal mucosal I/R damage in animal models [ 7 , 8 ], which proposing a new strategy for the management of intestinal I/R impairments. Therefore, the application of BMSCs in IR may be fruitful and have great clinical significance.…”

Inhibition of Cerebral Ischemia/Reperfusion Injury by MSCs-Derived Small Extracellular Vesicles in Rodent Models: A Systematic Review and Meta-Analysis

“…Mesenchymal stem cells (MSCs) possess the characteristics of immunoregulation, multidirectional differentiation potential, easy access, rapid proliferation in vitro, low activity loss after cryopreservation, low immunogenicity, and nontoxic side effects [ 5 ]. Several previous studies have demonstrated tremendous potential of MSCs in treating CIRI [ 6 ], myocardial ischemia-reperfusion injury (IRI) [ 7 ], hepatic IRI [ 8 ], intestinal IRI [ 9 ], renal IRI [ 10 ], lung IRI [ 11 ], retinal IRI [ 12 ], and spinal cord IRI [ 13 ] exhibiting specific mechanisms of action, such as angiogenesis, antiapoptosis, anti-inflammation, and tissue regeneration. In recent years, the literature supports that the paracrine mechanism of MSCs is mediated at least in part by extracellular vesicles (EVs) [ 14 ].…”