Dataset Information

Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells.

ABSTRACT:

Introduction

Although stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application. A need exists to maximize the therapeutic potential of these stem cells by first understanding what factors within the infarct microenvironment affect their ability to regenerate the necrotic tissue. In this study, we assessed both differentiation capacity and paracrine signaling as a function of extracellular matrix remodeling after myocardial infarction.

Methods

Mechanical and compositional changes to the decellularized infarcted myocardium were characterized to understand how the extracellular environment, specifically, was altered as a function of time after coronary artery ligation in Sprague-Dawley rats. These alterations were first modeled in a polyacrylamide gel system to understand how the variables of composition and stiffness drive mesenchymal stem cell differentiation towards a cardiac lineage. Finally, the paracrine secretome was characterized as a function of matrix remodeling through gene and protein expression and conditioned media studies.

Results

The decellularized infarct tissue revealed significant alterations in both the mechanical and compositional properties of the ECM with remodeling following infarction. This altered microenvironment dynamically regulates the potential for early cardiac differentiation. Whereas Nkx2.5 expression is limited in the presence of chronic remodeled matrix of increased stiffness, GATA4 expression is enhanced. In addition, the remodeled matrix promotes the expression of several proangiogenic, prosurvival, antifibrotic, and immunomodulatory growth factors. In particular, an increase in HGF and SDF1 expression and secretion by mesenchymal stem cells can rescue oxidatively stressed cardiomyocytes in vitro.

Conclusions

This study demonstrated that decellularization of diseased tissue allows for the exclusive analysis of the remodeled matrix and its ability to influence significantly the cellular phenotype. Characterization of cell fate as a function of myocardial remodeling following infarction is critical in developing the ideal strategy for cell implantation to maximize tissue regeneration and to ultimately reduce the prevalence and severity of heart failure.

SUBMITTER: Sullivan KE

PROVIDER: S-EPMC4055039 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells.

Sullivan Kelly Elizabeth KE Quinn Kyle Patrick KP Tang Katherine Michele KM Georgakoudi Irene I Black Lauren Deems LD

Stem cell research & therapy 20140124 1

<h4>Introduction</h4>Although stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application. A need exists to maximize the therapeutic potential of these stem cells by first understanding what factors within the infarct microenvironment affect their ability to regenerate the necrotic tissue. In this study, we assessed both differentiation capacity and paracrine signaling as a function of extracellula ...[more]

PMID: 24460869

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Project description:BackgroundThe two-dimensional incubation method is now the most commonly method for mesenchymal stem cell (MSC) production. however, gene expression and secretion of growth factors are relatively low; thus, the transplanted cells cannot be effectively utilized for potential clinical applications after acute myocardial infarction (AMI).ObjectivesWe aimed to investigate whether our newly made substrates of inverse opal with specific surface microstructures for MSC culturing can increase the viability of the cells and can contributes to decreased myocardial remodeling after transplanted to AMI mice.MethodsThe inverse opal structure is fabricated by the convenient bottom-up approach of the self-assembly of colloidal nanoparticles. Mouse-derived MSCs were then cultured on the substrates when expanded at different times to investigate the cell growth status including morphology. Then the inverse opal substrates loaded MSCs were transplanted to AMI mice, cardiomyocyte apoptosis and LV remodeling were further compared. To explore the possible mechanisms of curation, the secretions and viability of MSCs on substrates were determined using mice ELISA kits and JC-1 mitochondrial membrane potential assay kits respectively at normal and hypoxic conditions.Results6 times expanded inverse opals allowed greatly the orderly growth of MSCs as compared to four (34% ± 10.6%) and two (20%±7.2%) times expanded as well as unexpanded (13%±4.1%) (P<0.001). Nearly 90% of MSCs showed orientation angle intervals of less than 30° when at the 6X expanded (89.6%±25%) compared to the percent of cells with 30°-60° (8.7%±2.6%) or ≥60° (1.7%±1.0%) orientation angle (P<0.001). After inverse opal loaded MSCs transplanted to AMI mice, greatly decreased apoptosis of cardiomyocytes (20.45%±8.64% vs.39.63%±11.71%, P<0.001) and infarction area (5.87±2.18 mm2 vs 9.31±3.11 mm2, P<0.001) were identified. In the end, the viability of inverse opal loaded MSCs determined by membrane potential (P<0.001) and the secretion of growth factors including VEGF-α, SDF-1 and Ang-1 (P<0.001) were both confirmed significantly higher than that of the conventional culture in petri dish.ConclusionThe structure of inverse opal can not only adjust the arrangement of MSCs but also contribute to its orientated growth. Inverse opal loaded MSCs transplantation extremely curbed myocardial remodeling, the underlying mechanisms might be the high viability and extremely higher secretions of growth factors of MSCs as devoted by this method.

Project description:PurposeNitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.MethodsTo analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining.ResultsThree weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5) and end-diastolic volumes (82.7±5.6 μl; *p<0.05; n = 5) were significantly increased in BC-/EC+, along with decreased LV developed pressure (67.5±1.8 mm Hg; n = 18; ***p≤0.001) and increased scar size/left ventricle (19.5±1.5%; n = 13; **p≤0.01) compared to BC+/EC+ (ESV: 35.6±2.2 μl; EDV: 69.1±2.6 μl n = 8; LVDP: 83.2±3.2 mm Hg; n = 24; scar size/LV13.8±0.7%; n = 16). Myocardial scar of BC-/EC+ was characterized by increased total collagen content (20.2±0.8%; n = 13; ***p≤0.001) compared to BC+/EC+ (15.9±0.5; n = 16), and increased collagen type I and III subtypes.ConclusionCirculating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.

Dataset Information

Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells.

Introduction

Methods

Results

Conclusions

Publications

Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells.

Similar Datasets

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