Linking in vitro-to-in vivoToxicity Testing Using Genetically-matchedOrganoids and Mice from a Novel Genetic Reference Population

One of the long-standing challenges for toxicity testing and chemical safety evaluation is increasing throughput by using in vitro assays while at the same time improving the predictive power through in vitro-to-in vivo extrapolation (IVIVE) of exposure risk. Reprogramming of somatic cells into induced pluripotent stem cells (iPSC) permits generation of embryoid bodies (EB) with beating cardiomyocytes and complex cellular compositions similar to that found in vivo, making them a functional organotypic culture model (OCM). Importantly, iPSC-derived cardiomyocytes recapitulate phenotypic characteristics of cardiac disorders, which suggest that they have the potential to accurately represent individual chemical sensitivity when produced from a genetically heterogeneous population such as the innovative Collaborative Cross (CC) mouse genetic reference population. Overall, we reason the EB-OCM based on the CC is a perfect complement to human iPSC-derived cardiomyocytes for exploring predictive toxicity screening of environmental chemicals and evaluating risk assessment accuracy in a system where endpoints of in vitro OCM and in vivo individuals is known. Thus, the long-term objective of this research proposal is to identify characteristics of in vivo OCM assays that are most predictive of in vivo response to validate the OCM for IVIVE.