Inducing In Situ Functional Maturation of Transplanted Human Induced Pluripotent Stem Cell‐Derived Cardiomyocytes: Establishing Strategies for Treating Myocardial Injury

Abstract Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) have demonstrated significant potential for the treatment of heart diseases. However, hiPSC‐CMs generated by the current methods still exhibit structural and electrophysiological immaturity, resembling fetal cardiomyocytes. Although various strategies have been developed to promote in vitro maturation, cell loss and death remain persistent challenges during transplantation. Therefore, a multipronged approach is developed to induce in situ hiPSC‐CMs functional maturation and enhance the cell transplantation rate, not only allowing cells carried within to have lower automatism, but also retaining the ability to restore systolic function. Chitosan is used as the matrix backbone to form a unique 3D network structure for cell encapsulation and delivery, whereas anionic lipid‐based carriers derived from negatively charged liposomes enabled pH‐responsive release of the mammalian target of rapamycin (mTOR) inhibitor within the weakly acidic microenvironment in myocardial infarction. Inhibition of the mTOR‐signaling pathway can promote the functional maturation of hiPSC‐CMs by bringing them into a quiescent state, allowing the cells not only to have lower automatism but also to resume pulsation under slight stimulation. This approach promotes the functional recovery of injured hearts by enhancing more robust gap junctions and angiogenesis in infarcted mouse hearts.