Speaker — Qing Liu, Instructor, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, Calif.

Title — Human stem cells as a cell-based platform to study drug-induced developmental cardiotoxicity

Abstract — Maternal drug exposure during pregnancy increases the risks of congenital heart defects (CHDs). For instance, tyrosine kinase inhibitors (TKIs) are known to induce cardiotoxicity and mitochondrial dysfunction; they also can cross the placenta, posing high risks for CHDs. Here we used human embryonic stem cells (H1-hESCs) as an in-vitro system to investigate impacts of TKIs on cardiomyocyte (CM) differentiation. H1-hESCs were treated with several TKI drugs (imatinib, sunitinib, and vandetanib at sublethal levels) during CM differentiation. We found that developmental exposure to TKIs induced impairment of mitochondrial respiration, disarrangement of sarcomere structure, and significant alterations in contractility and Ca²⁺-handling properties of differentiating CMs. Computational biology analyses of both transcriptomic and chromatin accessibility landscape revealed that TKI-exposure altered GATA4-mediated regulatory network, which was highly correlated with mitochondrial functions. Using a gain-of-function approach with CRISPR-activation, we observed that increases in GATA4 expression restored CM functions and mitochondrial respiration despite of TKI exposure. Altogether, we applied a stem-cell-based system to identification of a novel crosstalk between GATA4 activity and mitochondrial respiration during CM differentiation. This study provides new insights into the relationship between gene-regulation and mitochondrial functions, and significantly enhances our understanding of sublethal TKI-induced cardiotoxicity during cardiac development.

Host — Carolyn Lawrence-Dill