Repairing chronic myocardial infarction with autologous mesenchymal stem cells engineered tissue in rat promotes angiogenesis and limits ventricular remodeling

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Abstract

Background

Tissue engineering scaffold constitutes a new strategy of myocardial repair. Here, we studied the contribution of a patch using autologous mesenchymal stem cells (MSCs) seeded on collagen-1 scaffold on the cardiac reconstruction in rat model of chronic myocardial infarction (MI).

Methods

Patches were cultured with controlled MSCs (growth, phenotype and potentiality). Twenty coronary ligated rats with tomoscingraphy (SPECT)-authenticated transmural chronic MI were referred into a control group (n = 10) and a treated group (n = 10) which beneficiated an epicardial MSC-patch engraftment. Contribution of MSC-patch was tested 1-mo after using non-invasive SPECT cardiac imaging, invasive hemodynamic assessment and immunohistochemistry.

Results

3D-collagen environment affected the cell growth but not the cell phenotype and potentiality. MSC-patch integrates well the epicardial side of chronic MI scar. In treated rats, one-month SPECT data have documented an improvement of perfusion in MI segments compared to control (64 ± 4% vs 49 ± 3% p = 0.02) and a reduced infarction. Contractile parameter dp/dtmax and dp/dtmin were improved (p & 0.01). Histology showed an increase of ventricular wall thickness (1.75 ± 0.24 vs 1.35 ± 0.32 mm, p &0.05) and immunochemistry of the repaired tissue displayed enhanced angiogenesis and myofibroblast-like tissue.

Conclusion

3D-MSC-collagen epicardial patch engraftment contributes to reverse remodeling of chronic MI.

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Most cited references 26

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Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.

Adam Williams, Joshua Hare (2011)

Mesenchymal stem cells (MSCs) are a prototypical adult stem cell with capacity for self-renewal and differentiation with a broad tissue distribution. Initially described in bone marrow, MSCs have the capacity to differentiate into mesoderm- and nonmesoderm-derived tissues. The endogenous role for MSCs is maintenance of stem cell niches (classically the hematopoietic), and as such, MSCs participate in organ homeostasis, wound healing, and successful aging. From a therapeutic perspective, and facilitated by the ease of preparation and immunologic privilege, MSCs are emerging as an extremely promising therapeutic agent for tissue regeneration. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSCs to engraft and differentiate into cardiomyocytes and vasculature cells, recruit endogenous cardiac stem cells, and secrete a wide array of paracrine factors. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. This article reviews the current understanding of MSC biology, mechanism of action in cardiac repair, translational findings, and early clinical trial data of MSC therapy for cardiac disease.

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Long term culture of mesenchymal stem cells in hypoxia promotes a genetic program maintaining their undifferentiated and multipotent status

Leticia Basciano, Christophe Nemos, Bernard Foliguet … (2011)

Background In the bone marrow, hematopietic and mesenchymal stem cells form a unique niche in which the oxygen tension is low. Hypoxia may have a role in maintaining stem cell fate, self renewal and multipotency. However, whereas most studies addressed the effect of transient in vitro exposure of MSC to hypoxia, permanent culture under hypoxia should reflect the better physiological conditions. Results Morphologic studies, differentiation and transcriptional profiling experiments were performed on MSC cultured in normoxia (21% O2) versus hypoxia (5% O2) for up to passage 2. Cells at passage 0 and at passage 2 were compared, and those at passage 0 in hypoxia generated fewer and smaller colonies than in normoxia. In parallel, MSC displayed (>4 fold) inhibition of genes involved in DNA metabolism, cell cycle progression and chromosome cohesion whereas transcripts involved in adhesion and metabolism (CD93, ESAM, VWF, PLVAP, ANGPT2, LEP, TCF1) were stimulated. Compared to normoxic cells, hypoxic cells were morphologically undifferentiated and contained less mitochondrias. After this lag phase, cells at passage 2 in hypoxia outgrew the cells cultured in normoxia and displayed an enhanced expression of genes (4-60 fold) involved in extracellular matrix assembly (SMOC2), neural and muscle development (NOG, GPR56, SNTG2, LAMA) and epithelial development (DMKN). This group described herein for the first time was assigned by the Gene Ontology program to "plasticity". Conclusion The duration of hypoxemia is a critical parameter in the differentiation capacity of MSC. Even in growth promoting conditions, hypoxia enhanced a genetic program that maintained the cells undifferentiated and multipotent. This condition may better reflect the in vivo gene signature of MSC, with potential implications in regenerative medicine.

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Contribution of extracellular matrix to the mechanical properties of the heart.

Gregory Fomovsky, Stavros Thomopoulos, Jeffrey W Holmes (2010)

Extracellular matrix (ECM) components play essential roles in development, remodeling, and signaling in the cardiovascular system. They are also important in determining the mechanics of blood vessels, valves, pericardium, and myocardium. The goal of this brief review is to summarize available information regarding the mechanical contributions of ECM in the myocardium. Fibrillar collagen, elastin, and proteoglycans all play crucial mechanical roles in many tissues in the body generally and in the cardiovascular system specifically. The myocardium contains all three components, but their mechanical contributions are relatively poorly understood. Most studies of ECM contributions to myocardial mechanics have focused on collagen, but quantitative prediction of mechanical properties of the myocardium, or changes in those properties with disease, from measured tissue structure is not yet possible. Circumstantial evidence suggests that the mechanics of cardiac elastin and proteoglycans merit further study. Work in other tissues used a combination of correlation, modification or digestion, and mathematical modeling to establish mechanical roles for specific ECM components; this work can provide guidance for new experiments and modeling studies in myocardium. 2009 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): J Biomed Sci

Journal ID (iso-abbrev): J. Biomed. Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date Collection: 2012

Publication date (Electronic): 12 November 2012

Volume: 19

Issue: 1

Page: 93

Affiliations

[1 ]Department of Cardiovascular Surgery, University of Lorraine, Nancy, France

[2 ]School of Surgery, Faculty of Medicine, University of Lorraine, Nancy, France

[3 ]INSERM, U961, University of Lorraine, Nancy, France

[4 ]Department of Nuclear Medicine, Nancyclotep, University of Lorraine, Nancy, France

[5 ]Service de Chirurgie Cardio-vasculaire, CHU-Nancy, Hôpital de Brabois, Allée du Morvan, Vandœuvre Cedex, 54511, France

Article

Publisher ID: 1423-0127-19-93

DOI: 10.1186/1423-0127-19-93

PMC ID: 3541342

PubMed ID: 23146158

SO-VID: fe103be3-cd0e-4df0-9175-907ebfe422b0

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Repairing chronic myocardial infarction with autologous mesenchymal stem cells engineered tissue in rat promotes angiogenesis and limits ventricular remodeling

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Abstract

Background

Methods

Results

Conclusion

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Most cited references 26

Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.

Long term culture of mesenchymal stem cells in hypoxia promotes a genetic program maintaining their undifferentiated and multipotent status

Contribution of extracellular matrix to the mechanical properties of the heart.

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