Restoring anisotropy after myocardial injury: strategies to align transplanted human induced pluripotent stem-cell-derived cardiomyocytes

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a promising cell source for cardiac regeneration, yet their therapeutic efficacy remains limited by poor structural organization and incomplete electromechanical integration after transplantation. A fundamental contribution to these limitations is made by the differences between the highly anisotropic architecture of native myocardium and the disorganized configuration of transplanted hiPSC-CMs. In the adult heart, cardiomyocyte alignment governs directional electrical conduction, coordinated contraction and efficient force transmission. In contrast, immature and poorly aligned hiPSC-CM grafts exhibit heterogeneous coupling, slowed or isotropic conduction and reduced functional integration. This review focuses on cardiomyocyte alignment as a critical design requirement for improving electrophysiological and regenerative outcomes in hiPSC-CM based cardiac cell therapy. We summarize bioengineering strategies that impose or preserve alignments, including topographical guidance, mechanical anisotropy, electrical conditioning and architectural delivery formats such as engineered tissues and cardiac patches. We further discuss how alignment influences intercellular junction organization, conduction anisotropy and graft-host integration and highlight the limitations of relying on global functional metrics that fail to capture directional electrical behaviour after transplantation. Collectively, this review argues that restoring myocardial anisotropy through engineered alignment is essential for translating hiPSC-CM immaturity towards functional and durable cardiac repair.