Multidimensional Platforms for Drug Discovery using Human Multicellular Cardiovascular Organoids for Heart Failure Prevention and Treatment

Introduction: Heart failure (HF) is a non-infectious pandemic affecting more than 2% of the general population worldwide. Research efforts heavily focus on treating HF in the final stages. Meanwhile, limited resources are allocated to HF prevention and for modifiers at early disease stages. While the induced pluripotent stem cell technology has been highly instrumental for modeling cardiac genetic diseases in which the mutated gene is expressed during early fetal life, it has been limited for modeling adult onset-cardiomyopathies. The main two limitations are the relatively immature phenotype of the generated cardiomyocytes which exhibit fetal-like characteristics and the insufficient structural and multicellular complexity of the cardiac tissue.

Methods: We generated a bioconvergent, multicellular, human, cardiovascular organoid platform based on human pluripotent stem cells. The organoids are composed of all authentic cellular components of the myocardium and undergo a step-wise maturation process at the tissue level. Functional evaluation of the organoid platform is conducted using a robotic system.

Results: Multicellular organoids formed included hiPSC based cardiomyocytes, endothelial cells and epicardial derived smooth muscle and cardiac fibroblast cells. Using a novel scheme for organoid maturation we have shown a significant increase in structural, functional and molecular markers of maturation coupled with the formation of a vessel network within the organoids. The generated organoids recapitulated the the cardiotoxic effects of anthracyclines and the protective effects of dexrazoxane. Using hypothesis-driven drug-repurposing screening we identified SGLT2i as a protective drug for preventing anthracycline toxicity. A second application of the generated organoid platform was to apply disease mimicking modules for emulating heart failure with preserved ejection fraction. The modules resulted in functional, molecular and structural properties recapitulating the HFpEF phenotype.

Summary: We generated authentic multicellular human cardiovascular organoids and applied novel maturation schemes at the multicellular environment. Multidimensional organoid platforms were used in order to model adult-onset, complex, acquired diseases such as chemotherapy induced cardiomyopathy and HFpEF. The generated platforms may be instrumental for gaining novel disease mechanistic insights and for the discovery of novel therapeutic targets.