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Pre-treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue.

ABSTRACT: Native myocardium consists of several cell types, of which approximately one-third are myocytes and most of the nonmyocytes are fibroblasts. By analogy with monolayer culture in which fibroblasts were removed to prevent overgrowth, early attempts to engineer myocardium utilized cell populations enriched for cardiac myocytes (CMs; approximately 80-90% of total cells). We hypothesized that the pre-treatment of synthetic elastomeric scaffolds with cardiac fibroblasts (CFs) will enhance the functional assembly of the engineered cardiac constructs by creating an environment supportive of cardiomyocyte attachment and function. Cells isolated from neonatal rat ventricles were prepared to form three distinct populations: rapidly plating cells identified as CFs, slowly plating cells identified as CMs, and unseparated initial population of cells (US). The cell fractions (3 x 10(6) cells total) were seeded into poly(glycerol sebacate) scaffolds (highly porous discs, 5 mm in diameter x 2-mm thick) using Matrigeltrade mark, either separately (CM or CF), concurrently (US), or sequentially (CF pre-treatment followed by CM culture, CF + CM), and cultured in spinner flasks. The CF + CM group had the highest amplitude of contraction and the lowest excitation threshold, superior DNA content, and higher glucose consumption rate. The CF + CM group exhibited compact 100- to 200-mum thick layers of elongated myocytes aligned in parallel over layers of collagen-producing fibroblasts, while US and CM groups exhibited scattered and poorly elongated myocytes. The sequential co-culture of CF and CM on a synthetic elastomer scaffold thus created an environment supportive of cardiomyocyte attachment, differentiation, and contractile function, presumably due to scaffold conditioning by cultured fibroblasts. When implanted over the infarcted myocardium in a nude rat model, cell-free poly(glycerol sebacate) remained at the ventricular wall after 2 weeks of in vivo, and was vascularized.

SUBMITTER: Radisic M

PROVIDER: S-EPMC2775086 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Pre-treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue.

Radisic Milica M Park Hyoungshin H Martens Timothy P TP Salazar-Lazaro Johanna E JE Geng Wenliang W Wang Yadong Y Langer Robert R Freed Lisa E LE Vunjak-Novakovic Gordana G

Journal of biomedical materials research. Part A 20080901 3

Native myocardium consists of several cell types, of which approximately one-third are myocytes and most of the nonmyocytes are fibroblasts. By analogy with monolayer culture in which fibroblasts were removed to prevent overgrowth, early attempts to engineer myocardium utilized cell populations enriched for cardiac myocytes (CMs; approximately 80-90% of total cells). We hypothesized that the pre-treatment of synthetic elastomeric scaffolds with cardiac fibroblasts (CFs) will enhance the function ...[more]

PMID: 18041719

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Project description:Complex heterocellular interactions between cardiomyocytes and fibroblasts in the heart involve their bidirectional signaling via cell-cell contacts, paracrine factors, and extracellular matrix (ECM). These interactions vary with heart development and pathology leading to changes in cardiac structure and function. Whether cardiac fibroblasts of different ages interact differentially with cardiomyocytes to distinctly impact their function remains unknown. Here, we explored the direct structural and functional effects of fetal and adult cardiac fibroblasts on cardiomyocytes using a tissue-engineered 3D co-culture system. We show that the age of cardiac fibroblasts is a strong determinant of the structure, function, and molecular properties of co-cultured tissues. In particular, in vitro expanded adult, but not fetal, cardiac fibroblasts significantly deteriorated electrical and mechanical function of the co-cultured cardiomyocytes, as evidenced by slower action potential conduction, prolonged action potential duration, weaker contractions, higher tissue stiffness, and reduced calcium transient amplitude. This functional deficit was associated with structural and molecular signatures of pathological remodeling including fibroblast proliferation, interstitial collagen deposition, and upregulation of pro-fibrotic markers. Our studies imply critical roles of the age of supporting cells in engineering functional cardiac tissues and provide a new physiologically relevant in vitro platform to investigate influence of heterocellular interactions on cardiomyocyte function, development, and disease.Previous studies have shown that cardiomyocytes and fibroblasts in the heart interact through direct contacts, paracrine factors, and matrix-mediated crosstalk. However, whether cardiac fibroblasts of different ages distinctly impact cardiomyocyte function remains elusive. We employed a tissue-engineered hydrogel-based co-culture system to study interactions of cardiomyocytes with fetal or adult cardiac fibroblasts. We show that the age of cardiac fibroblasts is a strong determinant of the structure, function, and molecular properties of engineered cardiac tissues and that key features of fibrotic myocardium are replicated by supplementing cardiomyocytes with expanded adult but not fetal fibroblasts. These findings relate to implantation of stem cell-derived cardiomyocytes in adult myocardium and warrant further studies of how age and source of non-myocytes impact cardiac function and maturation.

Dataset Information

Pre-treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue.

Publications

Pre-treatment of synthetic elastomeric scaffolds by cardiac fibroblasts improves engineered heart tissue.

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