Cadherin‐5 facilitated the differentiation of human induced pluripotent stem cells into sinoatrial node‐like pacemaker cells by regulating β‐catenin

Abstract Our study was conducted to investigate whether cadherin‐5 (CDH5), a vascular endothelial cell adhesion glycoprotein, could facilitate the differentiation of human induced pluripotent stem cells (hiPSCs) into sinoatrial node‐like pacemaker cells (SANLPCs), following previous findings of silk‐fibroin hydrogel‐induced direct conversion of quiescent cardiomyocytes into pacemaker cells in rats through the activation of CDH5. In this study, the differentiating hiPSCs were treated with CDH5 (40 ng/mL) between Day 5 and 7 during cardiomyocytes differentiation. The findings in the present study demonstrated that CDH5 stimulated the expression of pacemaker‐specific markers while suppressing markers associated with working cardiomyocytes, resulting in an increased proportion of SANLPCs among hiPSCs‐derived cardiomyocytes (hiPSC‐CMs) population. Moreover, CDH5 induced typical electrophysiological characteristics resembling cardiac pacemaker cells in hiPSC‐CMs. Further mechanistic investigations revealed that the enriched differentiation of hiPSCs into SANLPCs induced by CDH5 was partially reversed by iCRT14, an inhibitor of β‐catenin. Therefore, based on the aforementioned findings, it could be inferred that the regulation of β‐catenin by CDH5 played a crucial role in promoting the enriched differentiation of hiPSCs into SANLPCs, which presents a novel avenue for the construction of biological pacemakers in forthcoming research.