IGFBP2 Mediates Human iPSC-Cardiomyocyte Proliferation in a Cellular Contact-Dependent Manner

Inducing cardiomyocyte proliferation in situ presents a promising approach for cardiac regeneration following myocardial injury; however, mature cardiomyocytes exhibit inhibitory mechanisms that suppress proliferative signaling. This study investigates the role of cell-cell contact as a key regulator of cardiomyocyte proliferation. Using human iPSC-derived cardiomyocytes (hiPSC-CMs), the findings demonstrate that proliferation initially increases with cell density but is markedly suppressed upon the establishment of intercellular contacts. Phosphoproteomic and phenotypic analyses reveal that cell-cell contact promotes adherens junction formation, enhances sarcomere organization, and increases contractility, collectively contributing to the suppression of proliferation.