Dataset Information

Concomitant Retrograde Coronary Venous Infusion of Basic Fibroblast Growth Factor Enhances Engraftment and Differentiation of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair after Myocardial Infarction.

ABSTRACT:

Aim

Basic fibroblast growth factor (bFGF) increases the migration and viability of bone marrow mesenchymal stem cells (MSCs) in vitro. Retrograde coronary venous infusion can provide both increased regional bFGF concentrations and homogeneous cell dissemination. We determined whether retrograde delivery of bFGF enhances the potency of transplanted MSCs for cardiac repair in a canine infarct model.

Methods and results

Under hypoxic conditions, cellular migration was significantly increased in MSCs co-cultured with bFGF compared to vascular endothelial growth factor or insulin-like growth factor, and bFGF promoted MSCs differentiation into a cardiomyocyte phenotype. A canine infarct model was employed by coronary ligation. One week later, animals were subjected to retrograde infusion of combination bFGF (200ng/mL) and MSCs (1×10(8) cells) (n=5), MSCs (1×10(8) cells, n=5), bFGF (200ng/mL, n=5), or placebo (phosphate-buffered saline, n=3). Four weeks after infusion, only the bFGF+MSCs therapy exhibited significantly increased left ventricular ejection fraction (LVEF) by echocardiography (p<0.01 vs pre-infusion), and the treatment effect (delta LVEF) was greater in the bFGF+MSCs group compared to saline (7.43±1.51% versus -10.07±2.94%; p<0.001). Morphologic analysis revealed an increased infarct wall thickness in the bFGF+MSCs group compared to all others (p<0.05), accompanied by increased vascular density and reduced apoptosis. Immunofluorescence demonstrated increased cell engraftment and enhanced vascular differentiation in the bFGF+MSCs group compared to MSCs alone (p<0.05).

Conclusions

Retrograde coronary venous bFGF infusion augments engraftment and differentiation capacity of transplanted MSCs, recovering cardiac function and preventing adverse remodeling. This novel combined treatment and delivery method is a promising strategy for cardiac repair after ischemic injury.

SUBMITTER: Wang X

PROVIDER: S-EPMC4493537 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Concomitant Retrograde Coronary Venous Infusion of Basic Fibroblast Growth Factor Enhances Engraftment and Differentiation of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair after Myocardial Infarction.

Wang Xiao X Zhen Lei L Miao Huangtai H Sun Qiwei Q Yang Ya Y Que Bin B Lopes Lao Edmundo Patricio EP Wu Xingxin X Ren Hongmei H Shi Shutian S Lau Wayne B WB Ma Xinliang X Ma Changsheng C Nie Shaoping S

Theranostics 20150608 9

<h4>Aim</h4>Basic fibroblast growth factor (bFGF) increases the migration and viability of bone marrow mesenchymal stem cells (MSCs) in vitro. Retrograde coronary venous infusion can provide both increased regional bFGF concentrations and homogeneous cell dissemination. We determined whether retrograde delivery of bFGF enhances the potency of transplanted MSCs for cardiac repair in a canine infarct model.<h4>Methods and results</h4>Under hypoxic conditions, cellular migration was significantly i ...[more]

PMID: 26155315

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Project description:To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous (RCV) or arterial delivery.Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium.In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary (IC) delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either IC or RCV infusion of 10(7) (111)Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hr after cell delivery.IC delivery of porcine ASCs to normal myocardium was well tolerated up to a cumulative dose of 14 × 10(6) cells (approximately 0.5 × 10(6) cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50 × 10(6) ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, whereas at 10 × 10(6) ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hr with IC delivery compared with RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, P = 0.037) but this initial difference was not apparent at 24 hr (22.6 ± 5.5% vs. 18.7 ± 8.6%; P = 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hr postdelivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route.Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. IC arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise.

Project description:BackgroundMyocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an extracellular matrix (ECM) protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown.MethodsThree microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast-macrophage co-culture model in vitro.ResultsITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast-macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages.ConclusionsITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.

Dataset Information

Concomitant Retrograde Coronary Venous Infusion of Basic Fibroblast Growth Factor Enhances Engraftment and Differentiation of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair after Myocardial Infarction.

Aim

Methods and results

Conclusions

Publications

Concomitant Retrograde Coronary Venous Infusion of Basic Fibroblast Growth Factor Enhances Engraftment and Differentiation of Bone Marrow Mesenchymal Stem Cells for Cardiac Repair after Myocardial Infarction.

Similar Datasets

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