Targeting Dysregulated Maturation Program in PSC-Cardiomyocytes

Pluripotent-derived cardiomyocytes (PSC-CMs) remain immature in phenotype and function, and the lack of maturity has now emerged as a major concern in their clinical application. However, it remains poorly understood why PSC-CMs fail to fully mature. To address this, we have generated a high-quality, high-resolution single cell transcriptome map of endogenous CMs undergoing maturation and identified a critical window when a majority of genes change their expression levels. A direct transcriptomic integration with isogenic PSC-CMs has revealed a group of perinatal genes abnormally expressed in PSC-CMs, causing them to stall prematurely. Through comprehensive computational approaches, we further discovered a conserved gene regulatory network of dysregulated transcription factors that underlie maturation failure. In light of these findings, this project aims to test the role of the gene network in overcoming the premature arrest of PSC-CMs. This knowledge will pave the way for a transcriptome-based strategy for PSC-CM maturation, which can be leveraged towards improving clinical viability of PSC-CMs.