Guided Differentiation of Pluripotent Stem Cells for Cardiac Cell Diversity

Research aimed at characterizing and studying regulatory quantitative trait loci (QTLs) also shed light on phenotypic variation between individuals, including differences in disease risk and drug response. Regulatory QTL effects are highly context-dependent and may only manifest under a particular set of conditions. In principle, induced pluripotent stem cells (iPSCs) can differentiate into any cell type in the body, and when combined with single-cell RNA sequencing, iPSCs enable large-scale mapping of regulatory QTLs across different contexts. The challenge is to find a way to rapidly expand the dimensionality of cell types and cell states we can characterize. To address this, we developed a guided iPSC differentiation protocol that rapidly generates a temporally and functionally diverse range of cardiac-relevant cell types. In just 8-10 days, we consistently reproduce cardiac progenitors seen in laborious directed differentiation time-course studies, as well as terminal cell types that exist in mature cardiac organoids. Using guided differentiation, one can rapidly characterize regulatory variation and gene by environment interactions in spatially and temporally diverse cardiac cell types.