ABSTRACT Heart failure remains a leading cause of death worldwide, largely due to the myocardium's limited regenerative capacity. While the cardiac tissue engineering field aims to improve myocardial function following injury by implanting a cardiac graft, replicating the aligned architecture of the myocardium remains a significant challenge. This study presents an engineered platform for fabricating cardiac myobundles using a natural hydrogel composite containing synthetic, cell‐adhesive electrospun fibers to study the individual and synergistic roles of fiber reinforcement and cardiac fibroblasts. Our results demonstrate that cell‐adhesive fibers are essential for promoting cardiomyocyte (CM) spreading and myofibril assembly. Notably, induced pluripotent stem cell‐derived cardiac fibroblasts (iCFs) significantly outperformed primary cardiac fibroblasts (pCFs) in promoting tissue compaction via increased fibrinolytic activity, which was consistent across three distinct iPSC donor lines. Further, the combination of iCFs and cell‐adhesive fibers resulted in myobundles with enhanced CM spread area, myofibril formation, and contraction synchronicity; these results were also observed when extended to larger tissue grafts. Overall, this work identifies cell‐adhesive fibers as critical drivers of CM spreading, myofibril assembly, and CM contractile synchronicity, while determining the role of iCF‐mediated tissue compaction, collectively offering an improved method for developing large‐scale, functional myocardial grafts for the treatment of heart failure.
Jewett et al. (Sat,) studied this question.