Transcriptome Profiling of Patient-Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro

Abstract

SUMMARY Understanding individual susceptibility to drug-induced cardiotoxicity is key to improving patient safety and preventing drug attrition. Human induced pluripotent stem cells (hiPSCs) enable the study of pharmacological and toxicological responses in patient-specific cardiomyocytes (CMs), and may serve as preclinical platforms for precision medicine. Transcriptome profiling in hiPSC-CMs from seven individuals lacking known cardiovascular disease-associated mutations, and in three isogenic human heart tissue and hiPSC-CM pairs, showed greater inter-patient variation than intra-patient variation, verifying that reprogramming and differentiation preserve patient-specific gene expression, particularly in metabolic and stress-response genes. Transcriptome-based toxicology analysis predicted and risk-stratified patient-specific susceptibility to cardiotoxicity, and functional assays in hiPSC-CMs using tacrolimus and rosiglitazone, drugs targeting pathways predicted to produce cardiotoxicity, validated inter-patient differential responses. CRISPR/Cas9-mediated pathway correction prevented drug-induced cardiotoxicity. Our data suggest that hiPSC-CMs can be used in vitro to predict and validate patient-specific drug safety and efficacy, potentially enabling future clinical approaches to precision medicine.

Inspiration from heart development: Biomimetic development of functional human cardiac organoids

“…Despite immature characteristics of cardiac organoids compared to adult ventricular tissue, the presence of fundamental physiological cardiac functions provided a basis for exploring critical pathways involved in cardiac pathologies, supported by recent progress using hiPSC-CMs for cardiac pathophysiology insights (12, 86–89). Particularly, cardiac organoids have potential to serve as an in vitro cardiac model for ischemic heart failure, which makes up the majority of cardiovascular-related disorders (90).…”

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

“…From repairing damaged tissue in vivo to predicting drug efficacy, human pluripotent stem cells (hPSCs) have become a promising solution to many bottlenecks in human biological research [1][2][3][4][5][6] . There have been many efforts to generate cardiomyocytes (CMs) derived from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) due to the difficulty in obtaining human cardiac tissue by other methods 7 .…”

Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering

“…Additionally, hiPSC‐derived cardiomyocytes (hiPSC‐CM) were found to recapitulate phenotypic characteristics caused by genetic variations , which render these cells an suitable source for human disease models. Furthermore, hiPSC‐CM was found to be a powerful tool for patient stratification in regard to drug safety and responsiveness . To date, artificially matured patient‐derived hiPSC‐CM proved to be similar in to isolated primary human cardiomyocytes molecular, mechanical, electrophysiological, metabolic, and ultrastructural properties .…”

“…This is a strong argument to use edited hESC instead of patient‐specific hiPS cells, especially since each patient‐derived cell line has a very different genetic background from any other hiPSC line. Therefore, a familial control has to be used for every patient line, as was indicated by Matsa et al . In contrast, a single well defined hESC line (e.g., H9, H1, or HUES9) can be used as a basis for studies based on known mutations in which the unedited line can be a control for all introduced mutations.…”