000132268 001__ 132268 000132268 005__ 20240410085609.0 000132268 0247_ $$2doi$$a10.1021/acsbiomaterials.3c01302 000132268 0248_ $$2sideral$$a137431 000132268 037__ $$aART-2024-137431 000132268 041__ $$aeng 000132268 100__ $$0(orcid)0000-0001-6139-5905$$aPaz-Artigas, Laura 000132268 245__ $$aGeneration of Self-Induced Myocardial Ischemia in Large-Sized Cardiac Spheroids without Alteration of Environmental Conditions Recreates Fibrotic Remodeling and Tissue Stiffening Revealed by Constriction Assays 000132268 260__ $$c2024 000132268 5060_ $$aAccess copy available to the general public$$fUnrestricted 000132268 5203_ $$aA combination of human-induced pluripotent stem cells (hiPSCs) and 3D microtissue culture techniques allows the generation of models that recapitulate the cardiac microenvironment for preclinical research of new treatments. In particular, spheroids represent the simplest approach to culture cells in 3D and generate gradients of cellular access to the media, mimicking the effects of an ischemic event. However, previous models required incubation under low oxygen conditions or deprived nutrient media to recreate ischemia. Here, we describe the generation of large spheroids (i.e., larger than 500 μm diameter) that self-induce an ischemic core. Spheroids were generated by coculture of cardiomyocytes derived from hiPSCs (hiPSC-CMs) and primary human cardiac fibroblast (hCF). In the proper medium, cells formed aggregates that generated an ischemic core 2 days after seeding. Spheroids also showed spontaneous cellular reorganization after 10 days, with hiPSC-CMs located at the center and surrounded by hCFs. This led to an increase in microtissue stiffness, characterized by the implementation of a constriction assay. All in all, these phenomena are hints of the fibrotic tissue remodeling secondary to a cardiac ischemic event, thus demonstrating the suitability of these spheroids for the modeling of human cardiac ischemia and its potential application for new treatments and drug research. 000132268 536__ $$9info:eu-repo/grantAgreement/ES/MCINN/PID2022-139859OB-I00$$9info:eu-repo/grantAgreement/ES/MCIN/PLEC2021-008127$$9info:eu-repo/grantAgreement/ES/ISCIII/PI21-00946$$9info:eu-repo/grantAgreement/ES/ISCIII/PI19-01350$$9info:eu-repo/grantAgreement/ES/ISCIII CB16-11-00483$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 874827-BRAV3$$9info: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/BRAV3$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 848109-CRUCIAL$$9info:eu-repo/grantAgreement/EC/H2020/848109/EU/MiCrovasculaR rarefaction in vascUlar Cognitive Impairement and heArt faiLure/CRUCIAL$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 829010-PRIME$$9info:eu-repo/grantAgreement/EC/H2020/829010/EU/Advanced and versatile PRInting platform for the next generation of active Microfluidic dEvices/PRIME$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 778354-CISTEM$$9info:eu-repo/grantAgreement/EC/H2020/778354/EU/Heart On chip based on induced pluripotent Stem cell Technology for personalized Medicine/CISTEM 000132268 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/ 000132268 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000132268 700__ $$aGonzález-Lana, Sandra 000132268 700__ $$aPolo, Nicolás 000132268 700__ $$aVicente, Pedro 000132268 700__ $$aMontero-Calle, Pilar 000132268 700__ $$0(orcid)0000-0002-8375-0354$$aMartínez, Miguel A.$$uUniversidad de Zaragoza 000132268 700__ $$aRábago, Gregorio 000132268 700__ $$aSerra, Margarida 000132268 700__ $$aPrósper, Felipe 000132268 700__ $$aMazo, Manuel M. 000132268 700__ $$aGonzález, Arantxa 000132268 700__ $$aOchoa, Ignacio 000132268 700__ $$0(orcid)0000-0002-8666-622X$$aCiriza, Jesús$$uUniversidad de Zaragoza 000132268 7102_ $$11003$$2443$$aUniversidad de Zaragoza$$bDpto. Anatom.Histolog.Humanas$$cArea Histología 000132268 7102_ $$15004$$2605$$aUniversidad de Zaragoza$$bDpto. Ingeniería Mecánica$$cÁrea Mec.Med.Cont. y Teor.Est. 000132268 773__ $$g10, 2 (2024), 987-997$$pACS biomater. sci. eng.$$tACS BIOMATERIALS SCIENCE & ENGINEERING$$x2373-9878 000132268 8564_ $$s12544963$$uhttps://zaguan.unizar.es/record/132268/files/texto_completo.pdf$$yVersión publicada 000132268 8564_ $$s3228414$$uhttps://zaguan.unizar.es/record/132268/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000132268 909CO $$ooai:zaguan.unizar.es:132268$$particulos$$pdriver 000132268 951__ $$a2024-04-10-08:44:42 000132268 980__ $$aARTICLE