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Magnetic targeting enhances engraftment and functional benefit of iron-labeled cardiosphere-derived cells in myocardial infarction.

ABSTRACT: The success of cardiac stem cell therapies is limited by low cell retention, due at least in part to washout via coronary veins.We sought to counter the efflux of transplanted cells by rendering them magnetically responsive and imposing an external magnetic field on the heart during and immediately after injection.Cardiosphere-derived cells (CDCs) were labeled with superparamagnetic microspheres (SPMs). In vitro studies revealed that cell viability and function were minimally affected by SPM labeling. SPM-labeled rat CDCs were injected intramyocardially, with and without a superimposed magnet. With magnetic targeting, cells were visibly attracted toward the magnet and accumulated around the ischemic zone. In contrast, the majority of nontargeted cells washed out immediately after injection. Fluorescence imaging revealed more retention of transplanted cells in the heart, and less migration into other organs, in the magnetically targeted group. Quantitative PCR confirmed that magnetic targeting enhanced cell retention (at 24 hours) and engraftment (at 3 weeks) in the recipient hearts by approximately 3-fold compared to nontargeted cells. Morphometric analysis revealed maximal attenuation of left ventricular remodeling, and echocardiography showed the greatest functional improvement, in the magnetic targeting group. Histologically, more engrafted cells were evident with magnetic targeting, but there was no incremental inflammation.Magnetic targeting enhances cell retention, engraftment and functional benefit. This novel method to improve cell therapy outcomes offers the potential for rapid translation into clinical applications.

SUBMITTER: Cheng K

PROVIDER: S-EPMC2885138 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Magnetic targeting enhances engraftment and functional benefit of iron-labeled cardiosphere-derived cells in myocardial infarction.

Cheng Ke K Li Tao-Sheng TS Malliaras Konstantinos K Davis Darryl R DR Zhang Yiqiang Y Marbán Eduardo E

Circulation research 20100408 10

<h4>Rationale</h4>The success of cardiac stem cell therapies is limited by low cell retention, due at least in part to washout via coronary veins.<h4>Objective</h4>We sought to counter the efflux of transplanted cells by rendering them magnetically responsive and imposing an external magnetic field on the heart during and immediately after injection.<h4>Methods and results</h4>Cardiosphere-derived cells (CDCs) were labeled with superparamagnetic microspheres (SPMs). In vitro studies revealed tha ...[more]

PMID: 20378859

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Project description:: Although adipose-derived stem cells (ASCs) hold the promise of effective therapy for myocardial infarction, low cardiac retention of implanted ASCs has hindered their therapeutic efficiency. We investigated whether an externally applied static magnetic field (SMF) enhances cardiac localization of "magnetic" cells and promotes heart function recovery when ASCs are preloaded with superparamagnetic iron oxide (SPIO) nanoparticles. The influence of SMF (0.1 Tesla) on the biological activities of SPIO-labeled ASCs (SPIOASCs) was investigated first. Fifty-six female rats with myocardial infarction underwent intramyocardial injection of cell culture medium (CCM) or male SPIOASCs with or without the subcutaneous implantable magnet (CCM-magnet or SPIOASC-magnet). Four weeks later, endothelial differentiation, angiogenic cytokine secretion, angiogenesis, cardiomyocyte apoptosis, cell retention, and cardiac performance were examined. The 0.1-Tsela SMF did not adversely affect the viability, proliferation, angiogenic cytokine secretion, and DNA integrity of SPIOASCs. The implanted SPIOASCs could differentiate into endothelial cell, incorporate into newly formed vessels, and secrete multiple angiogenic cytokines. Four weeks after cell transplantation, the number of cardiac SPIOASCs was significantly increased, vascular density was markedly enlarged, fewer apoptotic cardiomyocytes were present, and heart contractile function was substantially improved in the SPIOASC-magnet treated rats in comparison with the SPIOASC-treated rats. The SPIOASCs could differentiate into endothelial cells, incorporate into vessels, promote angiogenesis, and inhibit ischemic cardiomyocyte apoptosis. An externally applied SMF offered a secure environment for biological properties of SPIOASCs, increased the cardiac retention of implanted magnetic SPIOASCs, and further enhanced heart function recovery after myocardial infarction.This pilot proof-of-concept study suggests that a 0.1-Tesla static magnetic field does not adversely affect the viability, proliferation, angiogenic cytokine secretion, or DNA integrity of the superparamagnetic iron oxide-labeled adipose-derived stem cells (SPIOASCs). Implantation of adipose-derived stem cells promotes myocardial neovascularization and inhibits ischemic cardiomyocyte apoptosis through endothelial differentiation, incorporation into vessels, and paracrine factor secretion. An externally applied static magnetic field enhanced myocardial retention of intramyocardially injected "magnetic" SPIOASCs and promoted cardiac function recovery after myocardial infarction. With further preclinical optimization, this approach may improve the outcome of current stem cell therapy for ischemic myocardial infarction.

Project description:Cell transplantation therapy will mean a breakthrough in resolving the donor shortage in cardiac transplantation. Cardiomyocyte (CM) transplantation, however, has been relatively inefficient in restoring cardiac function after myocardial infarction (MI) due to low engraftment of transplanted CM. In order to ameliorate engraftment of CM, the novel transplantation strategy must be invented. Gelatin hydrogel (GH) is a biodegradable water-soluble polymer gel. Gelatin is made of collagen. Although we observed that collagen strongly induced the aggregation of platelets to potentially cause coronary microembolization, GH did not enhance thrombogenicity. Therefore, GH is a suitable biomaterial in the cell therapy after heart failure. To assess the effect of GH on the improvement of cardiac function, fetal rat CM (5×10(6) or 1x10(6) cells) were transplanted with GH (10 mg/ml) to infarcted hearts. We compared this group with sham operated rats, CM in phosphate buffered saline (PBS), only PBS, and only GH-transplanted groups. Three weeks after transplantation, cardiac function was evaluated by echocardiography. The echocardiography confirmed that transplantation of 5×10(6) CM with GH significantly improved cardiac systolic function, compared with the CM+PBS group (fractional area change: 75.1±3.4% vs. 60.7±5.9%, p<0.05), only PBS, and only GH groups (60.1±6.5%, 65.0±2.8%, p<0.05). Pathological analyses demonstrated that in the CM+GH group, CM were efficiently engrafted in infarcted myocardium (p<0.01) and angiogenesis was significantly enhanced (p<0.05) in both central and peripheral areas of the scar. Moreover, quantitative RT-PCR revealed that angiogenic cytokines, such as basic fibroblast growth factor, vascular endothelial growth factor, and hepatocyte growth factor, were significantly enriched in the CM+GH group (p<0.05). Here, we report that GH confined the CM effectively in infarcted myocardium after transplantation, and that CM transplanted with GH improved cardiac function with a direct contraction effect and enhanced angiogenesis.

Project description:BACKGROUND:In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon's action on cardiac glucose and lipid homeostasis counteract that of insulin's action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI). METHODS:Male C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4 mg kg-1 week-1 starting at 1 week post-MI) for 3 weeks. RESULTS:Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0?±?2.3% vs 30.7?±?1.7% in vehicle-treated MI heart, p?<?0.05) and limited adverse remodelling (LV mass: 129?±?7 vs 176?±?14 mg in vehicle-treated MI hearts, p?<?0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661?±?192 vs 924?±?165 nmol g dry wt-1 min-1 in vehicle-treated MI hearts, p?<?0.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3? pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374?±?27 vs 183?±?41 µmol g protein-1 in vehicle-treated MI hearts, p?<?0.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor ?-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment. CONCLUSIONS:mAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.

Project description:Cardiosphere-derived stem cell (CDC) transplantation can improve global left ventricular ejection fraction (LVEF) after myocardial infarction (MI). The aim of this study was to examine the effects of CDC transplantation on regional function and dyssynchrony after MI.Two million rat CDCs (n = 7) or phosphate-buffered saline (n = 7) was injected into the infarct regions of Wistar Kyoto rats. Infarct size and CDC localization were evaluated by positron emission tomography (n = 7). Two-dimensional and strain echocardiography were performed at 1 and 4 weeks after MI. LVEF, circumferential strain, and time to peak circumferential strain were measured in the basal and apical short-axis views. Dyssynchrony was defined as the maximal difference of time to peak circumferential strain of opposing segments in each short-axis view. Engraftment was measured by quantitative polymerase chain reaction.Positron emission tomography revealed that infarct size was 15.4 ± 3.6% of the left ventricle and that CDCs were localized to the infarct and border zone. CDC transplantation improved mean LVEF (45 ± 8% to 52 ± 7%, P = .02), mean circumferential strain (-7 ± 2% to -10 ± 1%, P = .02), and mean dyssynchrony (45 ± 10 to 28 ± 11 m sec, P = .04) of the infarct/peri-infarct zone from 1 to 4 weeks after MI, despite CDC engraftment of only 2.4 ± 3%. In contrast, mean LVEF (48 ± 5% to 40 ± 4%, P = .03) and mean circumferential strain (-8 ± 2% to -7 ± 1%, P = .02) of the infarcted region deteriorated, with no significant change in dyssynchrony (42 ± 12 vs 46 ± 13 m sec, P = .60) in the saline group during the same time period. Change in LVEF was correlated with change in circumferential strain (r = -0.8, P = .002) and dyssynchrony (r = 0.6, P = .02) of the infarct/peri-infarct region at 4 weeks after MI.CDC therapy enhanced LVEF by improving circumferential strain and decreasing dyssynchrony of the infarct/peri-infarct region at 4 weeks, but not 1 week, after MI. Cellular resynchronization therapy using CDCs may be an alternative to traditional electrical cellular resynchronization therapy in post-MI dyssynchrony.

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Magnetic targeting enhances engraftment and functional benefit of iron-labeled cardiosphere-derived cells in myocardial infarction.

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Magnetic targeting enhances engraftment and functional benefit of iron-labeled cardiosphere-derived cells in myocardial infarction.

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