Distinct and Shared Determinants Impacting Cardiomyocyte Contractility in Multi-Lineage Competent Ethnically Diverse iPSCs

The promise of stem cell based therapeutic intervention in heart disease holds hope to improve long-term therapeutic outcomes, but is not yet realized. Strategies with bone marrow derived stem cells have been prevalent in clinical trials however other stem cell resources may offer advantages. The ability to use reprogrammed somatic cells for patient-optimized therapies, either from direct reprogramming to cardiac lineage or reprogramming first to pluripotent stem cells, requires expanding our understanding of how the epigenetic landscape affects downstream differentiation into cardiomyocytes or other specialized cardiac cells. Population diversity, including ethnicity should be included as resources become available. We derived multiple replicate iPSC lines from apparently healthy African American, Hispanic-Latino and Asian self-designated ethnically diverse (ED) origins and verified normal karyotype, teratoma formation, pluripotency biomarkers, and tri-lineage in vitro commitment. In multi-lineage derivation of cells of therapeutic interest we observed differences between replicate lines in efficiency to generate cardiomyocytes although similar and robust differentiation to multiple neural, pancreatic, and smooth muscle cell types. By bioinformatics of RNA-Seq and ChIP-seq pluripotency data sets for two replicate Asian and Hispanic-Latino ED-iPSC lines our analysis identified shared and distinct genes and contributing pathways in the replicate ED-iPSC lines. We further compared our analysis to larger genome wide association studies on ethnic populations to enhance our ability to understand how reprogramming to iPSC impacts genes and pathways contributing to cardiomyocyte contractility potential. In our analysis of cardiomyocytes we utilized custom lithography templated microarrays for quantitative assessment of multiple phenotypes. Smaller, yet data-rich analyses of ethnically diverse cell sets such as the data we generated on cardiomyocytes from ethnically diverse individuals, the first of its kind, are an important step and complement larger GWAS studies. In addition, in vitro models more readily provide genetic replicates versus the more complex phenotyping of large patient populations. The current study and data represent a new resource for continued investigation by the stem cell biomedical community and may find additional usefulness in bioengineered platforms for drug testing and metabolomics using ethnically diverse lines.