doi:10.1021/acsbiomaterials.3c01302engPaz-Artigas, LauraGonzález-Lana, SandraPolo, NicolásVicente, PedroMontero-Calle, PilarMartínez, Miguel A.Rábago, GregorioSerra, MargaridaPrósper, FelipeMazo, Manuel M.González, ArantxaOchoa, IgnacioCiriza, JesúsGeneration of Self-Induced Myocardial Ischemia in Large-Sized Cardiac Spheroids without Alteration of Environmental Conditions Recreates Fibrotic Remodeling and Tissue Stiffening Revealed by Constriction AssaysART-2024-137431A combination of human-induced pluripotent stem cells (hiPSCs) and 3D microtissue culture techniques allows the generation of models that recapitulate the cardiac microenvironment for preclinical research of new treatments. In particular, spheroids represent the simplest approach to culture cells in 3D and generate gradients of cellular access to the media, mimicking the effects of an ischemic event. However, previous models required incubation under low oxygen conditions or deprived nutrient media to recreate ischemia. Here, we describe the generation of large spheroids (i.e., larger than 500 μm diameter) that self-induce an ischemic core. Spheroids were generated by coculture of cardiomyocytes derived from hiPSCs (hiPSC-CMs) and primary human cardiac fibroblast (hCF). In the proper medium, cells formed aggregates that generated an ischemic core 2 days after seeding. Spheroids also showed spontaneous cellular reorganization after 10 days, with hiPSC-CMs located at the center and surrounded by hCFs. This led to an increase in microtissue stiffness, characterized by the implementation of a constriction assay. All in all, these phenomena are hints of the fibrotic tissue remodeling secondary to a cardiac ischemic event, thus demonstrating the suitability of these spheroids for the modeling of human cardiac ischemia and its potential application for new treatments and drug research.2024http://zaguan.unizar.es/record/13226810.1021/acsbiomaterials.3c01302http://zaguan.unizar.es/record/132268oai:zaguan.unizar.es:132268info:eu-repo/grantAgreement/EC/H2020/778354/EU/Heart On chip based on induced pluripotent Stem cell Technology for personalized Medicine/CISTEMThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 778354-CISTEMinfo:eu-repo/grantAgreement/EC/H2020/829010/EU/Advanced and versatile PRInting platform for the next generation of active Microfluidic dEvices/PRIMEThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 829010-PRIMEinfo:eu-repo/grantAgreement/EC/H2020/848109/EU/MiCrovasculaR rarefaction in vascUlar Cognitive Impairement and heArt faiLure/CRUCIALThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 848109-CRUCIALinfo:eu-repo/grantAgreement/EC/H2020/874827/EU/Computational biomechanics and bioengineering 3D printing to develop a personalized regenerative biological ventricular assist device to provide lasting functional support to damaged hearts/BRAV3This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 874827-BRAV3info:eu-repo/grantAgreement/ES/ISCIII CB16-11-00483info:eu-repo/grantAgreement/ES/ISCIII/PI19-01350info:eu-repo/grantAgreement/ES/ISCIII/PI21-00946info:eu-repo/grantAgreement/ES/MCIN/PLEC2021-008127info:eu-repo/grantAgreement/ES/MCINN/PID2022-139859OB-I00ACS BIOMATERIALS SCIENCE & ENGINEERING 10, 2 (2024), 987-997byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess