Transcriptome-based maturation assessment revealed pro-maturation transcription factors of cardiomyocytes

Induced pluripotent stem cell-derived cardiomyocytes have shown promise to be an essential tool for studying genetic cardiac diseases. However, their limited maturity remains a barrier to reaching their full potential. Many have challenged this problem; however, it is difficult to compare the results because the parameters for cardiomyocyte maturation are diverse, mostly relying on physiological experiments that display significant lab-to-lab variations and are labor-intensive, and are not comparable to maturing cardiomyocytes in vivo. Here, we propose a transcriptome-based scoring method for cardiomyocyte maturation. We first established the maturation score based on transcriptome of mouse ventricles from embryonic (day 11) to adult (10-month-old) ventricles. We then demonstrated that known maturation conditions increased the maturation scores of mouse embryonic stem cell-derived cardiomyocytes. We finally performed expression screening of 92 candidate transcriptional factors (TFs) and identified pro-maturation TFs, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), PGC1β, and estrogen-related receptor alpha (ERRα). These results support that the transcriptome-based maturation score is a quantitative and reliable approach for identifying pro-maturation factors for cardiomyocytes.