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IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction.

ABSTRACT: IL-18 is a proinflammatory cytokine known to cause tissue injury by inducing inflammation and cell death. Increased levels of IL-18 are associated with myocardial injury after ischemia or infarction. IL-18-binding protein (IL-18BP), the naturally occurring inhibitor of IL-18 activity, decreases the severity of inflammation in response to injury. In the present study, mesenchymal stem cells (MSCs) derived from mice transgenic for over expression of human IL-18BP were tested in rat models of global myocardial ischemia and acute myocardial infarction. Improved myocardial function is associated with production of VEGF, and in vitro, IL-18BP MSCs secreted higher levels of constitutive VEGF compared to wild-type MSCs. Whereas IL-18 increased cell death and reduced VEGF in wild-type MSCs, IL-18BP MSCs were protected. In an isolated heart model, intracoronary infusion of IL-18BP MSCs before ischemia increased postischemic left ventricular (LV) developed pressure to 79.5 + or - 9.47 mmHg compared to 59.3 + or - 7.8 mmHg in wild-type MSCs and 37.8 + or - 5 mmHg in the vehicle group. Similarly, using a coronary artery ligation model, intramyocardial injection of IL-18BP MSCs improved LV ejection fraction to 67.8 + or - 1.76% versus wild-type MSCs (57.4 + or - 1.33%) and vehicle (39.2 + or - 2.07%), increased LV fractional shortening 1.25-fold over wild-type MSCs and 1.95-fold over vehicle, decreased infarct size to 38.8 + or - 2.16% compared to 46.4 + or - 1.92% in wild-type MSCs and 60.7 + or - 2.2% in vehicle, reduced adverse ventricular remodeling, increased myocardial VEGF production, and decreased IL-6 levels. This study provides the concept that IL-18BP genetically modified stem cells improve cardioprotection over that observed with unmodified stem cells.

SUBMITTER: Wang M

PROVIDER: S-EPMC2752405 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProinflammatory cytokine cascades play crucial roles in the onset and progression of myocardial ischemia and infarction. Clinically, elevated serum levels of pro-inflammatory cytokine interleukin-6 is a poor prognostic indicator for future cardiac events and cardiac morbidity. Despite several reports, there is no clear evidence of cardiac benefits of inhibiting IL-6 in pre-clinical and clinical settings.ObjectiveTo analyze the available data systematically and perform a meta-analysis to show the evidence of effects of IL-6 inhibition on cardiac remodeling and mortality in ischemic animal models.MethodsWe used PICO framework and the quality of the studies was assessed using SYRCLE's risk of bias tool. Studies with interventions i.e., genetic deletion or pharmacological inhibition of IL-6/IL-6R were included for the meta-analysis. Systematic review was synthesized by including pre-clinical as well as randomized clinical trials involving myocardial infarction patients treated with IL-6 inhibitors. The effect size of the pooled data was determined using standard mean difference and 95% confidence intervals.ResultsA total of 12 pre-clinical studies were included in the review for analysis. Most of the studies showed an unclear risk of bias as the selection and reporting criteria were poorly described. We observed high heterogeneity in the included studies due to the varying duration of myocardial infarction and the dosage of IL-6 antibodies used in the studies. Overall inhibition of IL-6 significantly increased area at risk [p = 0.001, SMD = 0.49 (95% CI: -0.36, 1.35)] and significantly reduced ejection fraction [p = 0.001, SMD = -0.19 (95% CI: -1.39, 1.01)] and end-diastolic diameter [p = 0.02, SMD = -0.25 (95% CI: -0.87, 0.36)] of left ventricle post-MI, but no effects on infarct size [p < 0.01, SMD = 0.00; 95% CI: -1.34, 0.58). In randomized clinical trials, the overall effect on C-reactive protein remains significantly unchanged on CRP levels (SMD = -0.38; 95% CI: -1.94, 0.55) post-treatment with IL-6R inhibitor tocilizumab. The meta-regression demonstrates a significant positive correlation (p = 0.058) between the increase in ischemic area and duration of ischemia post-surgery in the absence of IL-6. This meta-analysis indicates mixed effect of IL-6 inhibition on cardiac remodeling post-MI, particularly in protecting the myocardium viability from damaging acute inflammation but not significant on cardiac function of ischemic animal models.ConclusionDespite the well-established pro-inflammatory nature of IL-6 in myocardial ischemia, our meta-analysis reports a limited contribution of IL-6 in the cardiac remodeling of hearts in animal models of myocardial ischemia. Moreover, genetically deleted IL-6 murine models produced contrasting results. Additional pre-clinical studies exploring the pharmacological inhibition of IL-6R are required to determine the beneficial effects of IL-6 inhibitors in regulating cardiac remodeling. The findings from IL-6R inhibition have better clinical relevance compared to genetically inhibited IL-6.

Project description:Acute myocardial infarction (AMI) is the most critical heart disease. Mesenchymal stem cells (MSCs) have been widely used as a therapy for AMI for several years. The human placenta has emerged as a valuable source of transplantable cells of mesenchymal origin that can be used for multiple cytotherapeutic purposes. However, the different abilities of first trimester placental chorion mesenchymal stem cells (FCMSCs) and third trimester placental chorion mesenchymal stem cells (TCMSCs) have not yet been explored. In this study, we aimed to compare the effectiveness of FCMSCs and TCMSCs on the treatment of AMI. FCMSCs and TCMSCs were isolated and characterized, and then they were subjected to in vitro endothelial cell (EC) differentiation induction and tube formation to evaluate angiogenic ability. Moreover, the in vivo effects of FCMSCs and TCMSCs on cardiac improvement were also evaluated in a rat MI model. Both FCSMCs and TCMSCs expressed a series of MSCs surface markers. After differentiation induction, FCMSCs-derived EC (FCMSCs-EC) exhibited morphology that was more similar to that of ECs and had higher CD31 and vWF levels than TCMSCs-EC. Furthermore, tube formation could be achieved by FCMSCs-EC that was significantly better than that of TCMSCs-EC. Especially, FCMSCs-EC expressed higher levels of pro-angiogenesis genes, PDGFD, VEGFA, and TNC, and lower levels of anti-angiogenesis genes, SPRY1 and ANGPTL1. In addition, cardiac improvement, indicated by left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVSF), could be observed following treatment with FCMSCs, and it was superior to that of TCMSCs and Bone marrow MSCs (BMSCs). FCMSCs exhibited a superior ability to generate EC differentiation, as evidenced by in vitro morphology, angiogenic potential and in vivo cardiac function improvement; further, increased levels of expression of pro-angiogenesis genes may be the mechanism by which this effect occurred.

Project description:BackgroundBone-derived mesenchymal stem cell (BMSC) transplantation has been reported to be effective for the treatment of ischemic heart disease, but whether BMSCs are the optimal cell type remains under debate. Increasing numbers of studies have shown that Nestin, an intermediate filament protein, is a potential marker for MSCs, which raises the question of whether Nestin+ cells in BMSCs may play a more crucial role in myocardial repair.MethodsNestin+ cells were isolated using flow cytometry by gating for CD45- Ter119- CD31- cells from the compact bone of Nestin-GFP transgenic mice, expressing GFP driven by the Nestin promoter. Colony-forming and proliferative curve assays were conducted to determine the proliferative capacity of these cells, while qRT-PCR was used to analyze the mRNA levels of relative chemokines and growth factors. Cardiac endothelial cell (CEC) recruitment was assessed via a transwell assay. Moreover, permanent ligation of the left anterior descending (LAD) coronary artery was performed to establish an acute myocardial infarction (AMI) mouse model. After cell transplantation, conventional echocardiography was conducted 1 and 4 weeks post-MI, and hearts were harvested for hematoxylin-and-eosin (HE) staining and immunofluorescence staining 1 week post-MI. Further evaluation of paracrine factor levels and administration of a neutralizing antibody (TIMP-1, TIMP-2, and CXCL12) or a CXCR4 antagonist (AMD3100) in MI hearts were performed to elucidate the mechanism involved in the chemotactic effect of Nestin+ BMSCs in vivo.ResultsCompared with Nestin- BMSCs, a greater proliferative capacity of Nestin+ BMSCs was observed, which further exhibited moderately high expression of chemokines instead of growth factors. More CEC recruitment in the Nestin+ BMSC-cocultured group was observed in vitro, while this effect was obviously abolished after treatment with neutralizing antibodies against TIMP-1, TIMP-2, or CXCL12, and more importantly, blocking the CXCL12/CXCR4 axis with a AMD3100 significantly reduced the chemotactic effect of Nestin+ BMSCs. After transplantation into mice exposed to myocardial infarction (MI), Nestin+ BMSC-treated mice showed significantly improved survival and left ventricular function compared with Nestin- BMSC-treated mice. Moreover, endogenous CECs were markedly increased, and chemokine levels were significantly higher, in the infarcted border zone with Nestin+ BMSC treatment. Meanwhile, neutralization of each TIMP-1, TIMP-2, or CXCL12 in vivo could reduce the left ventricular function at 1 and 4 weeks post-MI; importantly, the combined use of these three neutralizing antibodies could make a higher significance on cardiac function. Finally, blocking the CXCL12/CXCR4 axis with AMD3100 significantly reduced the left ventricular function and greatly inhibited Nestin+ BMSC-induced CEC chemotaxis in vivo.ConclusionsThese results suggest that Nestin+ BMSC transplantation can improve cardiac function in an AMI model by recruiting resident CECs to the infarcted border region via the CXCL12/CXCR4 chemokine pathway. And we demonstrated that Nestin+BMSC-secreted TIMP-1/2 enhances CXCL12(SDF1α)/CXCR4 axis-driven migration of endogenous Sca-1+ endothelial cells in ischemic heart post-AMI. Taken together, our results show that Nestin is a useful marker for the identification of functional BMSCs and indicate that Nestin+ BMSCs could be a better therapeutic candidate for cardiac repair.

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IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction.

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