Structural and functional remodeling of large-scale cardiac tubes.

Abstract

The functionality of tissue-engineered cardiac constructs using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is challenged by the cells' immature state. To promote cell and tissue maturation, co-culture approaches, mechanical, electrical and topographical stimuli have been applied. Here, large tubular constructs (6 x 1 cm) were engineered from hiPSC-CMs and human foreskin fibroblasts (ratio 9:1) via a rotating mold technology in four independent experiments. A maturation regimen employing progressive uniaxial stretch imposed on cardiac tubes by a custom-designed, cost-efficient, fully 3D printed stretching device ensured minimal manual intervention. Stepwise stretching (21% over 20 days) improved tissue contractility, alignment of hiPSC-CMs, sarcomere organization, and increased expression of cardiac structural genes, while maintaining tissue integrity and functionality in terms of spontaneous contractility and electrical responsiveness. The effect of modulating the stromal cell fraction on morphological and functional features of cardiac tubes was investigated in a pilot experiment. To more closely mimic native cardiac tissue and promote clinical translation, the originally applied human foreskin fibroblasts were replaced with hiPSC-derived cardiac fibroblast-like cells. Compared to planar cardiac tissues dominating the field, our results provide translational insights into tubular constructs, better reflecting aspects of the native heart. Our progress in large-scale tissue engineering and functional outcomes paves the way towards establishing clinically relevant biological cardiac assist devices.