Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell‐Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair

Abstract Stem cell‐based therapies have demonstrated significant potential for use in heart regeneration. An effective paradigm for heart repair in rodent and large animal models is the transplantation of human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs). Despite this, the functional and phenotypical immaturity of 2D‐cultured hiPSC‐CMs, particularly their low electrical integration, poses a caveat for clinical translation. In this study, a supramolecular assembly of a glycopeptide containing a cell adhesion motif‐RGD, and saccharide‐glucose (Bio‐Gluc‐RGD) is designed to enable the 3D spheroid formation of hiPSC‐CMs, promoting cell‐cell and cell‐matrix interactions that occur during spontaneous morphogenesis. HiPSC‐CMs in spheroids are prone to be phenotypically mature and developed robust gap junctions via activation of the integrin/ILK/p‐AKT/Gata4 pathway. Monodispersed hiPSC‐CMs encapsulated in the Bio‐Gluc‐RGD hydrogel are more likely to form aggregates and, therefore, survive in the infarcted myocardium of mice, accompanied by more robust gap junction formation in the transplanted cells, and hiPSC‐CMs delivered with the hydrogels also displayed angiogenic effect and anti‐apoptosis capacity in the peri‐infarct area, enhancing their overall therapeutic efficacy in myocardial infarction. Collectively, the findings illustrate a novel concept for modulating hiPSC‐CM maturation by spheroid induction, which has the potential for post‐MI heart regeneration.