TGF-β Signalling Drives Chemotaxis of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Response to MI Stimulus

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold significant promise for cardiac regeneration therapies. However, the efficacy of such treatments depends on the ability of transplanted cells to migrate and integrate into the damaged myocardium, a process that remains poorly understood. In this study, we investigated the migratory behaviour of hiPSC-CMs using homogenised rat MI tissue to simulate myocardial infarction (MI) in vitro. Transwell migration assays demonstrated a concentration-dependent chemotactic response, with hiPSC-CM migration increasing up to threefold toward MI tissue homogenate. Wound healing assays further confirmed enhanced migration under MI-mimetic conditions. Bulk RNA sequencing revealed activation of the TGF-{beta} signalling pathway as a key regulator of this response. Inhibition of TGF-{beta} signalling, both pharmacologically and through antibody neutralisation, significantly reduced hiPSC-CM migration. These findings uncover a previously underappreciated chemotactic capability of hiPSC-CMs and identify TGF-{beta} signalling as a central mediator, offering new mechanistic insights and potential therapeutic targets to improve the integration and efficacy of hiPSC-CM-based cardiac regeneration strategies.