Precision Health Resource of Control iPSC Lines for Versatile Multilineage Differentiation

Summary Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings.
Graphical Abstract
Highlights • Precision health resource of high-quality control iPSC lines for disease modeling • Versatile differentiation into six functional cell types shown by resource users • CRISPR gene editing reveals expected phenotype of cardiomyopathy model • Variant annotation identified preferred lines for neurologic and cardiac disease
Ellis, Scherer, and colleagues apply precision health to upgrade iPSC quality for disease modeling. The resource provides control lines from four healthy individuals, clinical annotation of whole-genome variants, and identification of variant-preferred lines for neurologic and cardiac disease. Resource users demonstrated versatile differentiation into functional cells from six tissues, and CRISPR-edited cells phenocopied a cardiomyopathy model.