Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells

Animal studies for embryotoxicity evaluation of potential therapeutics and environmental factors are complex, costly, and time-consuming. Often, studies are not of human relevance because of species differences. In the present study, we recapitulated the process of cardiomyogenesis in human induced pluripotent stem cells (hiPSCs) by modulation of the Wnt signaling pathway to identify a key cardiomyogenesis gene signature that can be applied to identify compounds and/or stress factors compromising the cardiomyogenesis process. Among the 23 tested teratogens and 16 non-teratogens, we identified three retinoids including 13-cis-retinoic acid that completely block the process of cardiomyogenesis in hiPSCs. Moreover, we have identified an early gene signature consisting of 31 genes and associated biological processes that are severely affected by the retinoids. To predict the inhibitory potential of teratogens and non-teratogens in the process of cardiomyogenesis we established the Developmental Cardiotoxicity Index (CDI31g) that accurately differentiates teratogens and non-teratogens to do or do not affect the differentiation of hiPSCs to functional cardiomyocytes.

Automated summary

Animal studies for embryotoxicity evaluation are limited in their relevance to humans due to species differences. This study used human induced pluripotent stem cells (hiPSCs) to recapitulate cardiomyogenesis and identify key genes and processes affected by potential teratogens. We found that certain retinoids completely blocked cardiomyogenesis in hiPSCs and established a Developmental Cardiotoxicity Index that accurately differentiates teratogens from non-teratogens.