Serine synthesis pathway regulates cardiac differentiation from human pluripotent stem cells [scRNA-seq]
Human induced pluripotent stem cells (hiPSCs) hold significant potential for advancing our understanding of heart development. Differentiating hiPSCs into cardiac cells allows for modeling early cardiac developmental processes and exploring key signaling pathways. However, variations in differentiation efficiency and poor reproducibility of hiPSC-derived cardiomyocytes (hiPSC-CMs) production have remained a challenge. Here, we report a unique metabolic method to promote hiPSC-CM differentiation that involves marked suppression of the mitochondrial oxidative phosphorylation from the mesendoderm to the cardiac mesoderm, which is regulated by PHGDH, a rate-limiting enzyme in the serine synthesis pathway (SSP). Mechanistically, the analysis of scRNA-seq revealed that SSP inhibition promotes CM lineage differentiation by disrupting the cardiopharyngeal mesoderm lineage differentiation. Our findings show that SSP can regulate cardiac differentiation and have implications in elucidating the potential mechanisms of heart development and pathogenesis of heart disease. Overall design: hiPSCs were differentiated into CMs. Cells were treated with DMSO or NCT-503 from Day 1 to Day 3 and collected on Days 1, 3, 5, and 9 for scRNA-seq.