Raniga, Kavita
(2024)
Development of multiparametric kinetic data and analytics workflows for the generation of an hiPSC-cardiomyocyte based cardiovascular model.
PhD thesis, University of Nottingham.
Abstract
It is widely acknowledged that many lifesaving drugs (e.g. cancer treatments) adversely affect the heart, potentially leading to irreversible myocardial injury and dysfunction. Drug-induced cardiotoxicity is characterized by functional and/or structural damage to the cardiovascular system and is a major reason for attrition during drug development. In the pharmaceutical industry, early-stage in vitro assessment of cardiovascular liabilities primarily centers around the assessment of cardiac function, using single-cell type-model systems. Over recent years, human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become an attractive platform for capturing the effects of putative drugs. The functional assessment of hiPSC-CMs for toxicity screening presents several limitations. Firstly, they lack the physiological responses to enable integrated risk assessment, such as phenotypic immaturity and the absence of cardiac vascular and/or stromal cells. Secondly, they require cellular manipulation, which interferes with cell function. For example, the use of a fluorescence calcium-sensitive dye can be cytotoxic with prolonged exposure. Lastly, they offer limited mechanistic insights for compound classes. These considerations are included in paper I (Raniga et al., Cell Stem Cell, 2023).
This thesis focused on improving the prediction of drug-induced cardiotoxicity by enhancing both functional and morphological assessments in vitro. Papers II, III, and IV focused on developing the tools required to establish an integrated multicellular in vitro model system for cardiotoxicity screening (2, Raniga et al., Methods in Molecular Biology, 2022; 3, Stebbeds, Raniga et al., Toxicological Sciences, 2023; and 4, Raniga et al., SLAS Discovery, 2023). Paper 5 (Raniga et al., in preparation) explored the feasibility of using a morphology-based profiling assay on hiPSC-CMs to provide further mechanistic insights into cardiotoxicity.
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