Abstract
Cardiac tissue engineering is a promising approach to treat cardiovascular diseases, which are a major socio-economic burden worldwide. An optimal material for cardiac tissue engineering, allowing cardiomyocyte attachment and exhibiting proper immunocompatibility, biocompatibility and mechanical characteristics, has not yet emerged. An additional challenge is to develop a fabrication method that enables the generation of proper hierarchical structures and constructs with a high density of cardiomyocytes for optimal contractility. Thus, there is a focus on identifying suitable materials for cardiac tissue engineering. Here, we investigated the interaction of neonatal rat heart cells with engineered spider silk protein (eADF4(C16)) tagged with the tripeptide arginyl-glycyl-aspartic acid cell adhesion motif RGD, which can be used as coating, but can also be 3D printed. Cardiomyocytes, fibroblasts, and endothelial cells attached well to eADF4(C16)-RGD coatings, which did not induce hypertrophy in cardiomyocytes, but allowed response to hypertrophic as well as proliferative stimuli. Furthermore, Kymograph and MUSCLEMOTION analyses showed proper cardiomyocyte beating characteristics on spider silk coatings, and cardiomyocytes formed compact cell aggregates, exhibiting markedly higher speed of contraction than cardiomyocyte mono-layers on fibronectin. The results suggest that eADF4(C16)-RGD is a promising material for cardiac tissue engineering.
Highlights
In 2016, cardiovascular disease (CVD) was responsible for approximately 17.6 million deaths worldwide, an increase of 14.5% compared to 2006
We have shown that materials made of silk fibroin of the silkworm Antheraea mylitta allow better cardiomyocyte attachment compared to materials made of Bombyx mori silk fibroin due to the presence of an intrinsic RGD-sequence[12], which is present in fibronectin[19], a natural component of the extracellular matrix of several organs[20], including the heart[21,22], on which neonatal rat cardiomyocytes have been shown to attach[23]
Since an integrin-binding RGD motif has been shown to promote cardiomyocyte attachment[12], we investigated cardiac cell behavior on coatings made of eADF4(C16)-RGD, a variant of eADF4(C16) in which an RGD-tag is fused C-terminally[29]
Summary
In 2016, cardiovascular disease (CVD) was responsible for approximately 17.6 million deaths worldwide, an increase of 14.5% compared to 2006. We have shown that materials made of silk fibroin of the silkworm Antheraea mylitta allow better cardiomyocyte attachment compared to materials made of Bombyx mori silk fibroin due to the presence of an intrinsic RGD-sequence[12], which is present in fibronectin[19], a natural component of the extracellular matrix of several organs[20], including the heart[21,22], on which neonatal rat cardiomyocytes have been shown to attach[23] Natural materials such as Antheraea mylitta silk show a highly variable quality due to factors such as living conditions and feeding, making their silk unsuitable for clinical applications[15]. EADF(κ16) enables attachment via its polycationic character, which may result in very different intracellular signaling processes
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