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Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction.

ABSTRACT: Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV-pretreated mesenchymal stem cells (MSCs) (ATV -MSCs) at 1?week post-acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of ATV -MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to determine the optimal time window for MSC treatment, we first assessed stromal cell-derived factor-1 (SDF-1) dynamic expression and inflammation. Next, we compared MSC recruitment and differentiation, cardiac function, infarct size, and angiogenesis among animal groups with single, dual, and triple injections of ATV -MSCs at early (Early1, Early2, Early3), mid-term (Mid1, Mid2, Mid3), and late (Late1, Late2, Late3) stages. Compared with AMI control, intensive ATV significantly augmented SDF-1 expression 1.5?2.6-fold in peri-infarcted region with inhibited inflammation. ATV -MSCs implantation with ATV administration further enhanced MSC recruitment rate by 3.9%?24.0%, improved left ventricular ejection fraction (LVEF) by 2.0%?16.2%, and reduced infarct size in all groups 6?weeks post-AMI with most prominent improvement in mid groups and still effective in late groups. Mechanistically, ATV -MSCs remarkably suppressed inflammation and apoptosis while increasing angiogenesis. Furthermore, triple injections of ATV -MSCs were much more effective than single administration during early and mid-term stages of AMI with the best effects in Mid3 group. We conclude that the optimal strategy is multiple injections of ATV -MSCs combined with intensive ATV administration at mid-term stage of AMI. The translational potential of this strategy is clinically promising. Stem Cells Translational Medicine 2019;8:1068-1083.

SUBMITTER: Xu J

PROVIDER: S-EPMC6766601 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction.

Xu Jun J Xiong Yu-Yan YY Li Qing Q Hu Meng-Jin MJ Huang Pei-Sen PS Xu Jun-Yan JY Tian Xia-Qiu XQ Jin Chen C Liu Jian-Dong JD Qian Li L Yang Yue-Jin YJ

Stem cells translational medicine 20190627 10

Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV-pretreated mesenchymal stem cells (MSCs) (<sup>ATV</sup> -MSCs) at 1 week post-acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of <sup>ATV</sup> -MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to de ...[more]

PMID: 31245934

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Project description:BackgroundExtracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV.MethodsMSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo.ResultsMSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy.ConclusionsWe uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Project description:BackgroundIn a swine model of acute myocardial infarction (AMI), Statins can enhance the therapeutic efficacy of mesenchymal stem cell (MSCs) transplantation. However, the mechanisms remain unclear. This study aims at assessing whether atorvastatin (Ator) facilitates the effects of MSCs through activation of nitric oxide synthase (NOS), especially endothelial nitric oxide synthase (eNOS), which is known to protect against ischemic injury.Methods and results42 miniswines were randomized into six groups (n = 7/group): Sham operation; AMI control; Ator only; MSC only, Ator+MSCs and Ator+MSCs+NG-nitrol-L-arginine (L-NNA), an inhibitor of NOS. In an open-heart surgery, swine coronary artery ligation and reperfusion model were established, and autologous bone-marrow MSCs were injected intramyocardium. Four weeks after transplantation, compared with the control group, Ator+MSCs animals exhibited decreased defect areas of both "perfusion" defined by Single-Photon Emission Computed Tomography (-6.2±1.8% vs. 2.0±5.1%, P = 0.0001) and "metabolism" defined by Positron Emission Tomography (-3.00±1.41% vs. 4.20±4.09%, P = 0.0004); Ejection fraction by Magnetic Resonance Imaging increased substantially (14.22±12.8% vs. 1.64±2.64%, P = 0.019). In addition, indices of inflammation, fibrosis, and apoptosis were reduced and survivals of MSCs or MSC-derived cells were increased in Ator+MSCs animals. In Ator or MSCs alone group, perfusion, metabolism, inflammation, fibrosis or apoptosis were reduced but there were no benefits in terms of heart function and cell survival. Furthermore, the above benefits of Ator+MSCs treatment could be partially blocked by L-NNA.ConclusionsAtorvastatin facilitates survival of implanted MSCs, improves function and morphology of infarcted hearts, mediated by activation of eNOS and alleviated by NOS inhibitor. The data reveal the cellular and molecular mechanism for anti-AMI therapy with a combination of statin and stem cells.

Project description:Most studies on intracoronary bone marrow mononuclear cell transplantation for acute myocardial infarction involve treatment 3-7 days after primary percutaneous coronary intervention (PCI); however, the optimal timing is unknown. The present study assessed the therapeutic effect at different times after ST-elevation myocardial infarction.The present trial was not blinded. A total of 104 patients with a first ST-elevation myocardial infarction and a left ventricular ejection fraction below 50 %, who had PCI of the infarct-related artery, were randomly assigned to receive intracoronary infusion of bone marrow mononuclear cells within 24 hours (group A, n = 27), 3 to 7 days after PCI (group B, n = 26), or 7 to 30 days after PCI (group C, n = 26), or to the control group (n = 25), which received saline infusion performed immediately after emergency PCI. All patients in groups A, B and C received an injection of 15 ml cell suspension containing approximately 4.9 × 10(8) bone marrow mononuclear cells into the infarct-related artery after successful PCI.Compared to control and group C patients, group A and B patients had a significantly higher absolute increase in left ventricular ejection fraction from baseline to 12 months (change: 3.4 ± 5.7 % in control, 7.9 ± 4.9 % in group A, 6.9 ± 3.9 % in group B, 4.7 ± 3.7 % in group C), a greater decrease in left ventricular end-systolic volumes (change: -6.4 ± 15.9 ml in control, -20.5 ± 13.3 ml in group A, -19.6 ± 11.1 ml in group B, -9.4 ± 16.3 ml in group C), and significantly greater myocardial perfusion (change from baseline: -4.7 ± 5.7 % in control, -7.8 ± 4.5 % in group A, -7.5 ± 2.9 % in group B, -5.0 ± 4.0 % in group C). Group A and B patients had similar beneficial effects on cardiac function (p = 0.163) and left ventricular geometry (left ventricular end-distolic volume: p = 0.685; left ventricular end-systolic volume: p = 0.622) assessed by echocardiography, whereas group C showed similar results to those of the control group. Group B showed more expensive care (p < 0.001) and longer hospital stays during the first month after emergency PCI (p < 0.001) than group A, with a similar improvement after repeat cardiac catheterization following emergency PCI.Cell therapy in acute myocardial infarction patients that is given within 24 hours is similar to 3-7 days after the primary PCI.NCT02425358 , registered 30 April 2015.

Project description:AimsNaturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms.Methods and resultsExosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSCATV-Exo) and were then delivered to endothelial cells and cardiomyocytes in vitro under hypoxia and serum deprivation (H/SD) condition or in vivo in an acutely infarcted Sprague-Dawley rat heart. Regulatory genes and pathways activated by ATV pretreatment were explored using genomics approaches and functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation, and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSCATV-Exo-treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSCATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSCATV-Exo promoted angiogenesis and inhibited the elevation of IL-6 and TNF-α in the peri-infarct region. Mechanistically, we identified lncRNA H19 as a mediator of the role of MSCATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and intercellular adhesion molecule-1. Consistently, the cardioprotective effects of MSCATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19.ConclusionExosomes obtained from ATV-pretreated MSCs have significantly enhanced therapeutic efficacy for treatment of AMI possibly through promoting endothelial cell function. LncRNA H19 mediates, at least partially, the cardioprotective roles of MSCATV-Exo in promoting angiogenesis.

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Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction.

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Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction.

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