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Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model.

ABSTRACT: Cell therapies have emerged as a promising treatment for the prevention of heart failure after myocardial infarction (MI). This study evaluated the capacity of an aligned, fibrin-based, stretch-conditioned cardiac patch consisting of either the native population or a cardiomyocyte (CM)-depleted population (i.e., CM+ or CM- patches) of neonatal rat heart cells to ameliorate left ventricular (LV) remodeling in the acute-phase postinfarction in syngeneic, immunocompetent rats. Patches were exposed to 7 days of static culture and 7 days of cyclic stretching prior to implantation. Within 1 week of implantation, both patches became vascularized, and non-CMs began migrating from CM+ patches. By week 4, patches had been remodeled into collagenous tissue, and live, elongated, donor CMs were found within grafted CM+ patches. Significant improvement in cardiac contractile function was seen with the administration of the CM+ patch (ejection fraction increased from 35.1% ± 4.0% for MI only to 58.8% ± 7.3% with a CM+ patch, p<0.05) associated with a 77% reduction in infarct size (61.3% ± 7.9% for MI only, 13.9% ± 10.8% for CM+ patch, p<0.05), and the elimination of LV free-wall thinning. Decreased infarct size and reduced wall thinning also occurred with the administration of the CM- patch (infarct size 36.9% ± 10.2%, LV wall thickness: 1058.2 ± 135.4 ?m for CM- patch, 661.3 ± 37.4 ?m for MI only, p<0.05), but without improvements in cardiac function. Approximately 36.5% of the transplanted CMs survived at 4 weeks; however, they remained separated and electrically uncoupled from the host myocardium by a layer of CM-free tissue, which suggests that the benefits of CM+ patch transplantation resulted from paracrine mechanisms originating from CMs. Collectively, these observations suggest that the transplantation of CM-containing engineered heart tissue patches can lead to dramatic improvements in cardiac function and remodeling after acute MI.

SUBMITTER: Wendel JS

PROVIDER: S-EPMC3993032 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model.

Wendel Jacqueline S JS Ye Lei L Zhang Pengyuan P Tranquillo Robert T RT Zhang Jianyi Jay JJ

Tissue engineering. Part A 20140206 7-8

Cell therapies have emerged as a promising treatment for the prevention of heart failure after myocardial infarction (MI). This study evaluated the capacity of an aligned, fibrin-based, stretch-conditioned cardiac patch consisting of either the native population or a cardiomyocyte (CM)-depleted population (i.e., CM+ or CM- patches) of neonatal rat heart cells to ameliorate left ventricular (LV) remodeling in the acute-phase postinfarction in syngeneic, immunocompetent rats. Patches were exposed ...[more]

PMID: 24295499

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Project description:UnlabelledA tissue-engineered cardiac patch provides a method to deliver cardiomyoctes to the injured myocardium with high cell retention and large, controlled infarct coverage, enhancing the ability of cells to limit remodeling after infarction. The patch environment can also yield increased survival. In the present study, we sought to assess the efficacy of a cardiac patch made from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to engraft and limit left ventricular (LV) remodeling acutely after infarction. Cardiac patches were created from hiPSC-CMs and human pericytes (PCs) entrapped in a fibrin gel and implanted acutely onto athymic rat hearts. hiPSC-CMs not only remained viable after in vivo culture, but also increased in number by as much as twofold, consistent with colocalization of human nuclear antigen, cardiac troponin T, and Ki-67 staining. CM+PC patches led to reduced infarct sizes compared with myocardial infarction-only controls at week 4, and CM+PC patch recipient hearts exhibited greater fractional shortening over all groups at both 1 and 4 weeks after transplantation. However, a decline occurred in fractional shortening for all groups over 4 weeks, and LV thinning was not mitigated. CM+PC patches became vascularized in vivo, and microvessels were more abundant in the host myocardium border zone, suggesting a paracrine mechanism for the improved cardiac function. PCs in a PC-only control patch did not survive 4 weeks in vivo. Our results indicate that cardiac patches containing hiPSC-CMs engraft onto acute infarcts, and the hiPSC-CMs survive, proliferate, and contribute to a reduction in infarct size and improvements in cardiac function.SignificanceIn the present study, a cardiac patch was created from human induced pluripotent stem cell-derived cardiomyocytes and human pericytes entrapped in a fibrin gel, and it was transplanted onto infarcted rat myocardium. It was found that a patch that contained both cardiomyocytes and pericytes survived transplantation and resulted in improved cardiac function and a reduced infarct size compared with controls.

Project description:BackgroundVentricular septal perforation and left ventricular aneurysm are examples of potentially fatal complications of myocardial infarction. While various artificial materials are used in the repair of these issues, the possibility of associated infection and calcification is non-negligible. Cell-seeded biodegradable tissue-engineered patches may be a potential solution. This study evaluated the feasibility of a new left ventricular patch rat model to study neotissue formation in biodegradable cardiac patches.MethodsHuman induced pluripotent stem cell-derived cardiac progenitor cells (hiPS-CPCs) were cultured onto biodegradable patches composed of polyglycolic acid and a 50:50 poly (l-lactide-co-ε-caprolactone) copolymer for one week. After culturing, patches were implanted into left ventricular walls of male athymic rats. Unseeded controls were also used (n = 10/group). Heart conditions were followed by echocardiography and patches were subsequently explanted at 1, 2, 6, and 9 months post-implantation for histological evaluation.ResultThroughout the study, no patches ruptured demonstrating the ability to withstand the high pressure left ventricular system. One month after transplantation, the seeded patch did not stain positive for human nuclei. However, many new blood vessels formed within patches with significantly greater vessels in the seeded group at the 6 month time point. Echocardiography showed no significant difference in left ventricular contraction rate between the two groups. Calcification was found inside patches after 6 months, but there was no significant difference between groups.ConclusionWe have developed a surgical method to implant a bioabsorbable scaffold into the left ventricular environment of rats with a high survival rate. Seeded hiPS-CPCs did not differentiate into cardiomyocytes, but the greater number of new blood vessels in seeded patches suggests the presence of cell seeding early in the remodeling process might provide a prolonged effect on neotissue formation. This experiment will contribute to the development of a treatment model for left ventricular failure using iPS cells in the future.

Project description:Functional cardiac tissue engineering holds promise as a candidate therapy for myocardial infarction and heart failure. Generation of "strong-contracting and fast-conducting" cardiac tissue patches capable of electromechanical coupling with host myocardium could allow efficient improvement of heart function without increased arrhythmogenic risks. Towards that goal, we engineered highly functional 1 cm × 1 cm cardiac tissue patches made of neonatal rat ventricular cells which after 2 weeks of culture exhibited force of contraction of 18.0 ± 1.4 mN, conduction velocity (CV) of 32.3 ± 1.8 cm/s, and sustained chronic activation when paced at rates as high as 8.7 ± 0.8 Hz. Patches transduced with genetically-encoded calcium indicator (GCaMP6) were implanted onto adult rat ventricles and after 4-6 weeks assessed for action potential conduction and electrical integration by two-camera optical mapping of GCaMP6-reported Ca2+ transients in the patch and RH237-reported action potentials in the recipient heart. Of the 13 implanted patches, 11 (85%) engrafted, maintained structural integrity, and conducted action potentials with average CVs and Ca2+ transient durations comparable to those before implantation. Despite preserved graft electrical properties, no anterograde or retrograde conduction could be induced between the patch and host cardiomyocytes, indicating lack of electrical integration. Electrical properties of the underlying myocardium were not changed by the engrafted patch. From immunostaining analyses, implanted patches were highly vascularized and expressed abundant electromechanical junctions, but remained separated from the epicardium by a non-myocyte layer. In summary, our studies demonstrate generation of highly functional cardiac tissue patches that can robustly engraft on the epicardial surface, vascularize, and maintain electrical function, but do not couple with host tissue. The lack of graft-host electrical integration is therefore a critical obstacle to development of efficient tissue engineering therapies for heart repair.

Project description:AIMS:The WNT/?-catenin pathway is temporarily activated in the heart following myocardial infarction (MI). Despite data from genetic models indicating both positive and negative roles for the WNT pathway depending on the model used, the effect of therapeutic inhibition of WNT pathway on post-injury outcome and the cellular mediators involved are not completely understood. Using a newly available, small molecule, GNF-6231, which averts WNT pathway activation by blocking secretion of all WNT ligands, we sought to investigate whether therapeutic inhibition of the WNT pathway temporarily after infarct can mitigate post injury cardiac dysfunction and fibrosis and the cellular mechanisms responsible for the effects. METHODS AND RESULTS:Pharmacologic inhibition of the WNT pathway by post-MI intravenous injection of GNF-6231 in C57Bl/6 mice significantly reduced the decline in cardiac function (Fractional Shortening at day 30: 38.71 ± 4.13% in GNF-6231 treated vs. 34.89 ± 4.86% in vehicle-treated), prevented adverse cardiac remodeling, and reduced infarct size (9.07 ± 3.98% vs. 17.18 ± 4.97%). WNT inhibition augmented proliferation of interstitial cells, particularly in the distal myocardium, inhibited apoptosis of cardiomyocytes, and reduced myofibroblast proliferation in the peri-infarct region. In vitro studies showed that WNT inhibition increased proliferation of Sca1+ cardiac progenitors, improved survival of cardiomyocytes, and inhibited collagen I synthesis by cardiac myofibroblasts. CONCLUSION:Systemic, temporary pharmacologic inhibition of the WNT pathway using an orally bioavailable drug immediately following MI resulted in improved function, reduced adverse remodeling and reduced infarct size in mice. Therapeutic WNT inhibition affected multiple aspects of infarct repair: it promoted proliferation of cardiac progenitors and other interstitial cells, inhibited myofibroblast proliferation, improved cardiomyocyte survival, and reduced collagen I gene expression by myofibroblasts. Our data point to a promising role for WNT inhibitory therapeutics as a new class of drugs to drive post-MI repair and prevent heart failure.

Dataset Information

Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model.

Publications

Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model.

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