Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine

Cell therapy treatment of myocardial infarction (MI) is mediated, in part, by exosomes secreted from transplanted cells. Thus, we compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after MI. Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium. In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5′-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.

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Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

Cell Death and Disease ◽

10.1038/s41419-021-03610-1 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

HuiYa Li ◽

DanQing Hu ◽

Guilin Chen ◽

DeDong Zheng ◽

ShuMei Li ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Paracrine Factors ◽

Dual Treatment

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

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Abstract 165: The 18 kDa FGF-2 Prevents the Doxorubicin-induced Cardiac Damage and Amp-activated Kinase Activation, in vitro and in vivo

Circulation Research ◽

10.1161/res.117.suppl_1.165 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Navid Koleini ◽

Jon Jon Santiago ◽

Barbara E Nickel ◽

Robert Fandrich ◽

Davinder S Jassal ◽

...

Keyword(s):

Molecular Weight ◽

Cell Death ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Wild Type ◽

Rat Cardiomyocytes ◽

Ventricular Ejection Fraction ◽

Compound C

Introduction: Protection of the heart from chemotherapeutic (Doxorubicin, DOX) drug-induced toxicity is a desirable goal, to limit side effects of cancer treatments. DOX toxicity has been linked to the activation (phosphorylation) of the AMP-activated kinase, AMPK. The 18 kDa low molecular weight isoform of fibroblast growth factor 2 (Lo-FGF-2) is a known cardioprotective and cytoprotective agent. In this study we have tested the ability of Lo-FGF-2 to protect from DOX-induced damage in rat cardiomyocytes in vitro, and in transgenic mouse models in vivo, in relation to AMPK activation. Methods: Rat neonatal cardiomyocytes in culture were exposed to DOX (0.5 μM) in the presence or absence of pre-treatment Lo-FGF-2 (10 ng/ml). Compound C was used to block phosphorylation (activity) of AMPK. Levels of cell viability/death (using Calcein-AM/Propidium iodide assay), phospho -and total AMPK, and apoptotic markers such as active caspase 3 were analyzed. In addition, transgenic mice expressing only Lo-FGF2, and wild type mice, expressing both high molecular weight (Hi-FGF2) as well as Lo-FGF2 were subjected to DOX injection (20 mg/kg, intraperitoneal); echocardiography was used to examine cardiac function at baseline and at 10 days post-DOX. Results: DOX-induced cell death of cardiomyocytes in culture was maximal at 24 hours post-DOX coinciding with significantly increased in activated (phosphorylated) AMPK. Compound C attenuated DOX-induced cardiomyocyte loss. Pre-incubation with Lo-FGF-2 decreased DOX induced cell death, and also attenuated the phosphorylation of AMPK post-DOX. Relative levels of phospho-AMPK were lower in the hearts of Lo-FGF2-expressing male mice compared to wild type. DOX-induced loss of contractile function (left ventricular ejection fraction and endocardial velocity) was negligible in Lo-FGF2-expressing mice but significant in wild type mice. Conclusion: Lo-FGF-2 protects the heart from DOX-induced damage in vitro and in vivo, by a mechanism likely involving an attenuation of AMPK activity.

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Abstract 15413: Building New Arteriogenic Therapy for Ischemic Cardiomyopathyusing Notch-induced Mesenchymal Stem Cell Patch

Circulation ◽

10.1161/circ.142.suppl_3.15413 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Shusaku Maeda ◽

Shigeru Miyagawa ◽

Takuji Kawamura ◽

Dai Chida ◽

Takashi Shibuya ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Notch Signaling ◽

Ischemic Cardiomyopathy ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ischemic Lesion

Introduction: The induction of arteriogenesis is a promising approach for treatment of ischemic cardiomyopathy. Notch signaling has been reported to be a key regulator of arteriogenesis. Hypothesis: We hypothesized that Notch-induced human mesenchymal stem cell (SB623) sheet transplantation would induce arteriogenesis in ischemic lesion, leading to improvement of left ventricular function in ischemic cardiomyopathy model rats. Methods: Two weeks after the ischemic induction, SB623-patches were transplanted to myocardial infarction model rats (SB group, n=10) or shame operations were performed (Control group, n=10). We evaluated cardiac performance and histology six weeks after the treatment in vivo. In vitro, we performed RNA-sequencing of human umbilical vein endothelial cells (HUVECs) cocultured with SB623s. Results: Left ventricular ejection fraction was significantly improved 6 weeks after SB623-sheets transplantation (LVEF, 52±7% vs. 34±5%, p<0.001). Similarly, the attenuation of LV remodeling was observed at 6 weeks (LV diastolic dimension, 73±7 mm vs. 85±5 mm, p<0.001). Histological findings revealed that fibrosis was decreased in SB group (11±1% vs. 22±4%, p=0.02). Furthermore, vWF-positive capillary vessels (vessels, 516±110 /mm 2 vs. 248±26 /mm 2 , p<0.001) and αSMA- and vWF-positive arterioles with over 20μm diameter (arterioles, 25±8 /mm 2 vs. 6±3 /mm 2 , p=0.002) were significantly increased in SB group, suggesting the induction of angiogenesis and arteriogenesis. In vitro, whole transcriptome analysis showed that Notch signaling pathway was significantly upregulated (p<0.001) in HUVECs co-cultured with SB623s. Similarly, pathway analysis revealed upregulated “fluid shear stress and atherosclerosis” pathway (p<0.001) in vitro, suggesting an arteriogenic response of endothelial cell. In vivo study, upregulations of ephrin-B2 (p=0.03) and EphB4 (p=0.01) gene expressions in SB group were confirmed, indicating both arterial and venous remodeling induced by Notch signaling. Conclusions: SB623 patch transplantation induces arteriogenesis with functional recovery via Notch signaling in rat myocardial infarction model, proposing a new strategy for the treatment of ischemic cardiomyopathy.

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Argon Exposure Induces Postconditioning in Myocardial Ischemia–Reperfusion

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248417702891 ◽

2017 ◽

Vol 22 (6) ◽

pp. 564-573 ◽

Cited By ~ 6

Author(s):

Sandrine Lemoine ◽

Katrien Blanchart ◽

Mathieu Souplis ◽

Adrien Lemaitre ◽

Damien Legallois ◽

...

Keyword(s):

Myocardial Infarction ◽

Ischemia Reperfusion ◽

Contractile Force ◽

Left Ventricular ◽

Border Zone ◽

Left Ventricular Ejection ◽

Human Atrial Appendages ◽

Hypoxia Reoxygenation

Background and Purpose: Cardioprotection against ischemia–reperfusion (I/R) damages remains a major concern during prehospital management of acute myocardial infarction. Noble gases have shown beneficial effects in preconditioning studies. Because emergency proceedings in the context of myocardial infarction require postconditioning strategies, we evaluated the effects of argon in such protocols on mammalian cardiac tissue. Experimental Approaches: In rat, cardiac I/R was induced in vivo by transient coronary artery ligature and cardiac functions were evaluated by magnetic resonance imaging. Hypoxia–reoxygenation (H/R)-induced arrhythmias were evaluated in vitro using intracellular microelectrodes on both rat-isolated ventricle and a model of border zone in guinea pig ventricle. Hypoxia–reoxygenation loss of contractile force was assessed in human atrial appendages. In those models, postconditioning was induced by 5 minutes application of argon at the time of reperfusion. Key Results: In the in vivo model, I/R produced left ventricular ejection fraction decrease (24%) and wall motion score increase (36%) which was prevented when argon was applied in postconditioning. In vitro, argon postconditioning abolished H/R-induced arrhythmias such as early after depolarizations, conduction blocks, and reentries. Recovery of contractile force in human atrial appendages after H/R was enhanced in the argon group, increasing from 51% ± 2% in the nonconditioned group to 83% ± 7% in the argon-treated group ( P < .001). This effect of argon was abolished in the presence of wortmannin and PD98059 which inhibit prosurvival phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and MEK/extracellular receptor kinase 1/2 (ERK 1/2), respectively, or in the presence of the mitochondrial permeability transition pore opener atractyloside, suggesting the involvement of the reperfusion injury salvage kinase pathway. Conclusion and Implications: Argon has strong cardioprotective properties when applied in conditions of postconditioning and thus appears as a potential therapeutic tool in I/R situations.

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Abstract 542: Chronic Doxorubicin Cardiotoxicity Assessed in Engineered Cardiac Tissues Generated in Biowire™ II Platform

Circulation Research ◽

10.1161/res.127.suppl_1.542 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Roozbeh Aschar-sobbi ◽

Julia E Napolitano ◽

Danielle R Bogdanowicz ◽

Michael P Graziano

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Cardiac Fibroblasts ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Resting Membrane Potential ◽

Ventricular Ejection Fraction ◽

Cardiac Tissues

The anthracycline doxorubicin is an effective anti-tumor agent widely used in both adults and children. One major adverse effect of doxorubicin therapy is dose-dependent cardiotoxicity, ranging from asymptomatic reduction in left ventricular ejection fraction to more serious, potentially fatal symptoms including arrythmias and congestive heart failure. The exact mechanism of doxorubicin-induced cardiotoxicity remains unknown. Recently, human induced pluripotent stem cells (hiPSC) have emerged as a potential tool to model cardiac toxicity, but their fetal-like phenotype raises concerns about the translatability of in vitro data to in vivo cardiotoxicity. To overcome this limitation, Biowire™ II platform was used to generate 3D engineered cardiac tissues (ECTs) from hiPSC-derived cardiomyocytes and human cardiac fibroblasts. Using long-term electrical stimulation, ECTs with a phenotype approaching that of adult human myocardium were obtained. The ECTs were then exposed to 1 μM doxorubicin for 8 days followed by 7 days of washout. Measurements of contractile force amplitude at 1 Hz stimulation showed a transient increase in force within 24 hours of doxorubicin exposure followed by decrease in force after 2 days. Intracellular recordings of action potential (AP) showed a decrease in maximum upstroke velocity (dV/dt), AP amplitude (APA), and resting membrane potential (RMP) after 8 days of doxorubicin treatment. In addition, action potential duration (APD) at 30% (APD30) repolarization was increased in doxorubicin-treated ECTs, whereas APD50 and APD90 were decreased. Following 7 days of washout, no difference in force or AP parameters was found between doxorubicin and vehicle-treated ECTs with the exception of APD50 and APD90 which remained abbreviated. A global untargeted analysis of the conditioned media from doxorubicin-treated ECTs identified 204 analytes and revealed an upregulation of redox homeostasis, differential fatty acid metabolism, altered glycolysis and TCA cycle metabolites, and decreased nucleoside metabolism compared to vehicle-treated ECTs. These results show that doxorubicin not only increases oxidative stress, but also irreversibly affects action potential duration which may predispose to cardiac arrhythmias.

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CD51 distinguishes a subpopulation of bone marrow mesenchymal stem cells with distinct migratory potential: a novel cell-based strategy to treat acute myocardial infarction in mice

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1439-y ◽

2019 ◽

Vol 10 (1) ◽

Author(s):

Dong-Mei Xie ◽

Yuan-Long Li ◽

Jie Li ◽

Qinglang Li ◽

Guihua Lu ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Bone Marrow ◽

Intravenous Injection ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Differentiation Potential ◽

Migratory Capacity

Abstract Background Experimental and clinical trials have demonstrated the efficiency of bone marrow-derived mesenchymal stromal/stem cells (bMSCs) in the treatment of myocardial infarction. However, after intravenous injection, the ineffective migration of engrafted bMSCs to the hearts remains an obstacle, which has an undesirable impact on the efficiency of cell-based therapy. Therefore, we attempted to identify a marker that could distinguish a subpopulation of bMSCs with a promising migratory capacity. Methods Here, CD51-negative and CD51-positive cells were isolated by flow cytometry from Ter119−CD45−CD31−bMSCs and cultured in specifically modified medium. The proliferation ability of the cells was evaluated by 5-ethynyl-2′-deoxyuridine (EdU) staining or continuously monitored during culture, and the differentiation potential was assessed by culturing the cells in the appropriate conditioned media. Wound healing assays, transwell assays and quantitative polymerase chain reaction (qPCR) were used to measure the migratory ability. The mice were subjected to a sham operation or myocardial infarction (MI) by permanently occluding the coronary artery, and green fluorescent protein (GFP)-labelled cells were transplanted into the mice via intravenous infusion immediately after MI. Heart function was measured by echocardiography; infarct myocardium tissues were detected by triphenyl tetrazolium chloride (TTC) staining. Additionally, immunofluorescence staining was used to verify the characteristics of CD51+bMSCs and inflammatory responses in vivo. Statistical comparisons were performed using a two-tailed Student’s t test. Results In this study, the isolated CD51−bMSCs and CD51+bMSCs, especially the CD51+ cells, presented a favourable proliferative capacity and could differentiate into adipocytes, osteocytes and chondrocytes in vitro. After the cells were transplanted into the MI mice by intravenous injection, the therapeutic efficiency of CD51+bMSCs in improving left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) was better than that of CD51−bMSCs. Compared with CD51−bMSCs, CD51+bMSCs preferentially migrated to and were retained in the infarcted hearts at 48 h and 8 days after intravenous injection. Accordingly, the migratory capacity of CD51+bMSCs exceeded that of CD51−bMSCs in vitro, and the former cells expressed higher levels of chemokine receptors or ligands. Interestingly, the retained CD51+bMSCs retained in the myocardium possessed proliferative potential but only differentiated into endothelial cells, smooth muscle cells, fibroblasts or cardiomyocytes. Transplantation of CD51+bMSCs partially attenuated the inflammatory response in the hearts after MI, while the potential for inflammatory suppression was low in CD51−bMSC-treated mice. Conclusions These findings indicated that the CD51-distinguished subpopulation of bMSCs facilitated proliferation and migration both in vitro and in vivo, which provided a novel cell-based strategy to treat acute MI in mice by intravenous injection.

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Hypoxic-conditioned cardiosphere-derived cell sheet transplantation for chronic myocardial infarction

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezz122 ◽

2019 ◽

Vol 56 (6) ◽

pp. 1062-1074

Author(s):

Akira Fujita ◽

Koji Ueno ◽

Toshiro Saito ◽

Masashi Yanagihara ◽

Hiroshi Kurazumi ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Cell Sheet ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Enzyme Linked Immunosorbent Assay ◽

Chronic Myocardial Infarction ◽

Ventricular Ejection Fraction ◽

Paracrine Effects

Abstract OBJECTIVES Cell therapy provides a suitable environment for regeneration through paracrine effects such as secretion of growth factors. Cardiosphere-derived cells (CDCs) have a high capacity for growth factor secretion and are an attractive target for clinical applications. In particular, a cell sheet technique was reported to have clinical advantages by covering a specific region. Here, we examined the effect of the hypoxic-conditioned (HC) autologous CDC sheet therapy on a rabbit chronic myocardial infarction model. METHODS CDC sheet function was assessed by the enzyme-linked immunosorbent assay and quantified by polymerase chain reaction in vitro (days 1–3 of conditioning). The rabbit chronic myocardial infarction model was established by left coronary ligation. Autologous CDCs were isolated from the left atrial specimen; CDC sheets with or without 2-day HC were transplanted onto the infarcted hearts at 4 weeks. The cardiac function was assessed by an echocardiography at 0, 4 and 8 weeks. A histological analysis of the host hearts was performed by tomato lectin staining at 8 weeks. RESULTS The optimal HC duration was 48 h. HC significantly increased the mRNA expression levels of VEGF and ANG2 on day 2 compared to the normoxic-conditioned (NC) group. The HC group showed significant improvement in the left ventricular ejection fraction (64.4% vs 58.8% and 53.4% in the NC and control) and a greater lectin-positive area in the ischaemic region (HC:NC:control = 13:8:2). CONCLUSIONS HC enhances the paracrine effect of a CDC sheet on angiogenesis to improve cardiac function in the chronic myocardial infarction model, which is essential for cardiomyocyte proliferation during cardiac regeneration.

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Abstract 209: Ketone Bodies Ameliorate Cardiac Function in Heart Failure

Circulation ◽

10.1161/circ.142.suppl_4.209 ◽

2020 ◽

Vol 142 (Suppl_4) ◽

Author(s):

Jessica Gambardella ◽

Marco B. Morelli ◽

Xujun Wang ◽

Gaetano Santulli

Keyword(s):

Cardiac Function ◽

Ketone Bodies ◽

Left Ventricular ◽

Cardiac Cells ◽

Left Ventricular Ejection ◽

Standard Diet ◽

Apoptotic Pathway ◽

Ventricular Ejection Fraction ◽

Cardiac Phenotype

Background: Beta hydroxibutirrate (BHB) is the main ketone body produced during fasting or carbohydrate deprivation as an alternative fuel. Mounting evidence suggests that after myocardial infarction (MI), the mitochondrial impairment and metabolic failure coincide with increased levels and utilization of BHB. However, whether the BHB increase is adaptive or maladaptive in damaged myocardium, has never been evaluated. Aim: Our scope was to explore the effects of BHB on cardiac function after ischemia both in vivo and in vitro . Methods and Results: In cultured cardiomyoblasts, the administration of BHB (3 mMol) reduces the activation of caspase-3 in response to ischemia, as well as the number of tunnel positive nuclei. Specifically, the mitochondrial apoptotic pathway seems affected, as BHB reduces cytochrome-C release induced by ischemia. Mitochondrial structure and interconnections, soundly affected by ischemia, were significantly retained in presence of BHB, as well as mitochondrial membrane potential (assessed via TMRE). The preserved mitochondrial health was further supported by higher levels of PGC1-alpha detected in cells exposed to ischemia plus BHB compared to ischemia alone. To explore the in vivo effects of BHB on ischemia damaged- myocardium, we administrated carbohydrate-null diet ( ketogenic diet , KD) or standard diet-supplemented with BHB, to post-MI mice. Both groups treated with KD and BHB supplemented diet displayed preserved left ventricular ejection fraction respect to untreated infarcted mice. The protective effects of BHB on cardiac phenotype were mirrored by increased levels of PGC1-alpha in the myocardium of treated mice, in terms of protein and transcription levels. Interestingly, in the hearts of mice fed KD and BHB supplemented diet, we observed a marked difference in histone acetylation pattern. Conclusions: BHB protects cardiac cells from apoptotic and mitochondrial damage induced by ischemia. Through its ability to regulate epigenetic modifications, BHB could activate a gene expression program able to support mitochondrial function, thereby representing a powerful therapeutic strategy.

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Abstract 13347: Injectable Collagen-based Hydrogel Matrix Modulates Micro-RNA Expression and Prevents Cardiac Deterioration Post-myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.13347 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Nick J Blackburn ◽

Brian McNeill ◽

Helene Chiarella-Redfern ◽

Tanja Sofrenovic ◽

Drew Kuraitis ◽

...

Keyword(s):

Myocardial Infarction ◽

Left Ventricular ◽

Post Treatment ◽

Left Ventricular Ejection ◽

Type I ◽

Injectable Hydrogel ◽

Ventricular Ejection Fraction ◽

Hydrogel Matrix ◽

The Matrix

Background: Injectable hydrogel biomaterials have emerged as promising therapies for treating myocardial infarction (MI). We developed a collagen type I based injectable hydrogel matrix that can prevent the deterioration of cardiac function when delivered soon post-MI and found that the effects may be mediated through a microRNA (miRNA) mechanism. Methods/Results: C57BL/6J mice underwent LAD ligation to induce MI. Mice then received myocardial injections of PBS or matrix delivered at 3hours post-MI. Analyses were performed at 2 days, 1 and 3 months post-treatment. At one month post-treatment, mice that received the matrix had superior left ventricular ejection fraction (LVEF; 45.1±2.3%) compared to the PBS group (29.6±2.4%; p< 0.001). LVEF was maintained in matrix-treated mice at 3 months (42.9±3.8%). Matrix treatment was also associated with reduced infarct sizes and improved ventricular volumes. Matrix-treated mice had more angiogenesis, mitigated apoptosis and reduced inflammation in the infarcted myocardium at both 2 and 28 days post-treatment. To better understand the mechanisms, we performed miRNA microarrays on infarct and peri-infarct tissue. Matrix treatment resulted in 120 miRNAs with differential expression within +/- 0.3 log2 fold change. In particular, we found matrix treatment down-regulated miR-92a ( p< 0.0005), an anti-angiogenic miRNA. Integrins α5 (Itgα5) and αV (ItgαV), involved in angiogenesis and cell-matrix interactions, were identified as putative miR-92a targets and pursued further in vitro using circulating angiogenic cells (CACs). CACs cultured on the matrix had increased Itgα5 and ItgαV expression after 4 days (12.4-fold and 13.9-fold, respectively vs. fibronectin; p< 0.01). When applied in an in vitro angiogenesis assay, the number of CACs that incorporated into capillary-like structures was greater (by 4.2-fold) for cells derived from matrix culture ( p <0.005). Conclusion: We demonstrate pronounced benefits associated with our hydrogel matrix when delivered at 3h post-MI. The matrix effects may be mediated, at least in part, through its ability to regulate miR-92a and integrin-mechanisms. Overall, the matrix may provide a promising therapeutic approach for protecting the myocardium post-MI.

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Recovery of Infarcted Myocardium in an In Vivo Experiment

Medicina ◽

10.3390/medicina47110088 ◽

2011 ◽

Vol 47 (11) ◽

pp. 88 ◽

Cited By ~ 1

Author(s):

Raimondas Širmenis ◽

Antanas Kraniauskas ◽

Rasa Jarašienė ◽

Daiva Baltriukienė ◽

Audronė Kalvelytė ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Cardiac Function ◽

Rabbit Heart ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Infarcted Myocardium ◽

Myogenic Stem Cells

Acute myocardial infarction leads to the loss of functional cardiomyocytes and structural integrity. The adult heart cannot repair the damaged tissue due to inability of mature cardiomyocytes to divide and lack of stem cells. The aim of this study was to evaluate the efficiency of introduced autologous skeletal musclederived stem cells to recover the function of acutely infarcted rabbit heart in the early postoperative period. Material and Methods. As a model for myocardium restoration in vivo, experimental rabbit heart infarct was used. Autologic adult myogenic stem cells were isolated from skeletal muscle and propagated in culture. Before transplantation, the cells were labeled with 4´,6-diamidino-2-phenylindole and then, during heart surgery, introduced into the rabbit acutely infarcted myocardium. Postoperative cardiac function was monitored by recording electrocardiograms and echocardiograms. At the end of the experiment, the efficiency of cell integration was evaluated histologically. Results. Rabbit cardiac function recovered after 1 month after the induction of experimental infarction both in the control and experimental groups. Therefore, the first month after the infarction was the most significant for the assessment of cell transplantation efficacy. Transplanted cell integration into infarcted myocardium was time- and individual-dependent. Evaluation of changes in left ventricular ejection fraction after the induction of myocardial infarction revealed better recovery in the experimental group; however, the difference among animals in the experimental and control groups varied and was not significant. Conclusions. Autologous myogenic stem cells repopulated infarcted myocardium with different efficiency in each individual. This variability may account for the observed difference in postoperative cardiac recovery in a rabbit model.

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