To understand the intrinsic cardiac developmental and functional abnormalities in pulmonary atresia with the intact ventricular septum (PAIVS) free from effects secondary to anatomic defects, we performed and compared single‐cell transcriptomic and phenotypic analyses of patient‐ and healthy subject–derived human‐induced pluripotent stem cell-derived cardiomyocytes (hiPSC‐CMs) and engineered tissue models.
We derived hiPSC lines from 3 patients with PAIVS and three healthy subjects. We differentiated them into hiPSC‐CMs, which were then bioengineered into the human cardiac anisotropic sheet and human cardiac tissue strip custom‐designed for electrophysiological and contractile assessments, respectively. Single‐cell RNA sequencing (scRNA‐seq) of hiPSC‐CMs, human cardiac anisotropic sheet, and human cardiac tissue strip was performed to examine the transcriptomic basis for any phenotypic abnormalities using pseudotime and differential expression analyses.
In conclusion, single‐cell transcriptomics and cardiac tissue engineering of patient‐specific hiPSC‐CMs reveal an abnormal developmental trajectory and intrinsic contractile defects in HRHS. The novel mechanistic insights based on our findings illustrate the importance of intrinsic abnormalities of cardiomyocytes as a cause of cardiac dysfunction in the absence of postnatal secondary remodeling in congenital structural malformations and set the stage for modeling other complex congenital cardiac anomalies using patient‐specific hiPSCs.
Ref: https://www.ahajournals.org/doi/10.1161/JAHA.120.016528
