Mechanically induced pyroptosis enhanced cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy

Abstract Cellular oxidative stress resistance and bioactivities showed great significance for long-term survival and cardiac regeneration. Cardiosphere-derived cells (CDCs) are favorable cell sources for myocardial infarction (MI) therapy, but effective culture systems for CDC spheroids, cardiospheres (CSps), cultivation and cell function enhancement are not well established. Here, a liquid crystal substrate, octyl hydroxypropyl cellulose ester (OPC), was developed for CSps production and preconditioning. With unique surface properties and mechanical responsiveness, significantly more size-controllable CSps were acquired using OPC substrate, and the OPC-CSps showed improved cell bioactivities and oxidative stress resistance under the stimulation of mechanical-induced pyroptosis. RNA sequencing and metabolism analysis demonstrated the increased metabolic level and improved mitochondrial function of OPC-CSps. In a rat MI model, OPC-CSps significantly improved long-term cardiac function, promoted angiogenesis, and reduced cardiac remodeling in the 3-month observation. Collectively, this study provides a promising and effective system for preparing massive functional CSps for myocardial infarction therapy.