Available online 29 October 2024The functional restoration of a damaged cardiac tissue relies on a synchronized contractile capacity of exogenous and/or endogenous cardiomyocytes, which is challenging to achieve. Here, we explored the potential of the short glycopeptide diphenylalanine glucosamine-6-sulfate (FFGlcN6S) conjugated with an aromatic moiety, namely fluorenylmethoxycarbonyl (Fmoc), to enhance cardiac tissue regeneration. At physiological conditions, Fmoc-FFGlcN6S assembles into nanofibrous hydrated meshes, i.e., matrix mimicking hydrogels. These hydrogels can be further micropatterned allowing co-existence of hierarchical structures at different scales. The patterned hydrogels support the culture of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and promote their alignment. The cultured iPSC-CMs exhibit anisotropic synchronized contractions, indicating maturation and electrical interconnectivity. Moreover, the cultures express specific cardiac markers including, connexin-43 and sarcomeric-α-actinin, confirming enhanced cell-cell crosstalk, spontaneous contractility, and efficient transmission of electrical signals. Our results showcase the potential of short amphiphilic glycopeptides to mimic physical and biochemical cues that are essential for cardiomyocytes functionality and thus, these conjugates can be used in cardiac tissue engineering and regeneration.The authors acknowledge the European Commission and the Portuguese Foundation for Science and Technology for financial support: RAP- CEECINST/00077/2018 and 2022.05623.CEECIND; VIBC – PD/BD/135256/2017; DC - 2023.06285.CEECIND; COVID/BD/152018/2021; M-ERA-NET3/0007/2021 (RePark). We also acknowledge PluriCell Biotech for the supply of the cardiomyocytes derived from induced pluripotent stem cells, and the project “TERM RES Hub – Scientific Infrastructure for Tissue Engineering and Regenerative Medicine” -PINFRA/22190/2016 (Norte-01-0145-FEDER-022190, co-funded by FCT and the Northern Portugal Regional Coordination and Development Commission, CCDR-N), for providing lab facilities, state-of-the art equipment and highly qualified human resources
