Abstract P1117: Personalized Care Using Patient-derived Cardiac Spheroids For Heart Failure Patients

Abstract

Preclinical studies using currently available in vitro and in vivo models fail at fully recapitulating the in vivo human heart microenvironment and its pathophysiology, limiting their translation from the bench to the bedside. Our laboratory has developed cardiac spheroids (CSs) as advanced in vitro models of the human heart using cardiac myocytes, endothelial cells and fibroblasts at ratios approximating the ones found in the human heart. Thanks to patient-derived induced pluripotent stem cells (iPSCs), we have quickly moved to personalized CSs to establish advanced pathophysiological in vitro models of heart failure (HF). CSs have been used to evaluate short- and long-term effects of ischaemic/reperfusion (I/R) injury typical of myocardial infarction (MI), drug-induced toxicity, SARS-CoV-2 exposure and pregnancy-induced HF. This was achieved using our established protocols to induce I/R-mimic injury, as well by exposing CSs to doxorubicin (DOX), SARS-CoV-2 virus and pre-eclampsia blood samples, respectively. First, our analyses of cell toxicity ratios using calcein-AM and ethidium homodimer (staining live and dead cells, respectively) demonstrated treatment-specific loss in cell viability and increase in cell death compared to control (untreated, healthy) CSs. Other CSs stained with ethidium homodimer and cell-specific antibodies were imaged and further used for 3D rendering analyses using IMARIS software. This enabled us to identify cell-specific responses in each pathological condition. Then, our measurements of fractional shortening and contraction frequency in CSs showed a statistically significant loss of contractile function in treated CSs compared to controls. Finally, new potential targets to prevent myocardial injury were evaluated using transcriptomics analyses, with a focus on changes in expression levels for genes regulating sarcomere structure, calcium transport, cell cycle, cardiac remodelling and signal transduction. Current studies are evaluating novel potential therapeutic targets to prevent and treat myocardial injury in HF patients using CSs. This has the potential to pave the way to prevent and treat HF in a safer and personalised way, hopefully preventing undesired effects due to non-specific care.