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Phenotypic Variation Between Stromal Cells Differentially Impacts Engineered Cardiac Tissue Function.

ABSTRACT: IMPACT STATEMENT:Understanding the relationship between parenchymal and supporting cell populations is paramount to recapitulate the multicellular complexity of native tissues. Incorporation of stromal cells is widely recognized to be necessary for the stable formation of stem cell-derived cardiac tissues; yet, the types of stromal cells used have varied widely. This study systematically characterized several stromal populations and found that stromal phenotype and morphology was highly variable depending on cell source and exerted differential impacts on cardiac tissue function and induced pluripotent stem cell-cardiomyocyte phenotype. Therefore, the choice of supporting stromal population can differentially impact the phenotypic or functional performance of engineered cardiac tissues.

SUBMITTER: Hookway TA

PROVIDER: S-EPMC6535958 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Phenotypic Variation Between Stromal Cells Differentially Impacts Engineered Cardiac Tissue Function.

Hookway Tracy A TA Matthys Oriane B OB Mendoza-Camacho Federico N FN Rains Sarah S Sepulveda Jessica E JE Joy David A DA McDevitt Todd C TC

Tissue engineering. Part A 20190501 9-10

<h4>Impact statement</h4>Understanding the relationship between parenchymal and supporting cell populations is paramount to recapitulate the multicellular complexity of native tissues. Incorporation of stromal cells is widely recognized to be necessary for the stable formation of stem cell-derived cardiac tissues; yet, the types of stromal cells used have varied widely. This study systematically characterized several stromal populations and found that stromal phenotype and morphology was highly ...[more]

PMID: 30968748

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Project description:Cardiac tissue engineering has been working to alleviate the immense burden of cardiovascular disease for several decades. To improve cardiac tissue homogeneity and cardiomyocyte (CM) maturation, in this study, we investigated altering initial encapsulation geometry in a three-dimensional (3D) direct cardiac differentiation platform. Traditional engineered cardiac tissue production utilizes predifferentiated CMs to produce 3D cardiac tissue and often involves various cell selection and exogenous stimulation methods to promote CM maturation. Starting tissue formation directly with human induced pluripotent stem cells (hiPSCs), rather than predifferentiated CMs, simplifies the engineered cardiac tissue formation process, making it more applicable for widespread implementation and scale-up. In this study, hiPSCs were encapsulated in poly (ethylene glycol)-fibrinogen in three tissue geometries (disc-shaped microislands, squares, and rectangles) and subjected to established cardiac differentiation protocols. Resulting 3D engineered cardiac tissues (3D-ECTs) from each geometry displayed similar CM populations (∼65%) and gene expression over time. Notably, rectangular tissues displayed less tissue heterogeneity and suggested more advanced features of maturing CMs, including myofibrillar alignment and Z-line formation. In addition, rectangular tissue showed significantly higher anisotropic contractile properties compared to square and microisland tissues (MI 0.28 ± 0.03, SQ 0.35 ± 0.05, RT 0.79 ± 0.04). This study demonstrates a straightforward method for simplifying and improving 3D-ECT production without the use of exogenous mechanical or electrical pacing and has the potential to be utilized in bioprinting and drug testing applications. Impact statement Current methods for improving cardiac maturation postdifferentiation remain tedious and complex. In this study, we examined the impact of initial encapsulation geometry on improvement of three-dimensional engineered cardiac tissue (3D-ECT) production and postdifferentiation maturation for three tissue geometries, including disc-shaped microislands, squares, and rectangles. Notably, rectangular 3D-ECTs displayed less tissue heterogeneity and more advanced features of maturing cardiomyocytes, including myofibrillar alignment, Z-line formation, and anisotropic contractile properties, compared to microisland and square tissues. This study demonstrates an initial human induced pluripotent stem cell-encapsulated rectangular tissue geometry can improve cardiac maturation, rather than implementing cell selection or tedious postdifferentiation manipulation, including exogenous mechanical and/or electrical pacing.

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

Phenotypic Variation Between Stromal Cells Differentially Impacts Engineered Cardiac Tissue Function.

Publications

Phenotypic Variation Between Stromal Cells Differentially Impacts Engineered Cardiac Tissue Function.

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