Final Report Summary - CHD-IPS (Modeling congenital heart disease (CHD) in ISL1+ cardiovascular progenitors from patient-specific iPS cells)
Furthermore, we employed patient-specific induced pluripotent stem cells (hiPSCs) to investigate perturbations of human cardiac progenitor biology in CHDs. Whole exome-sequencing of patients affected by hypoplastic Left Heart Syndrome (hLHS) in combination with transcriptional and proteomic profiling of cardiac lineages from hLHS iPSCs revealed an unexpected role of cilia and cell cycle regulation in the disease etiology. These findings were validated in multiple systems including i) ex vivo patient heart biopsies, ii) in vitro human cardiogenesis in iPSCs and iii) fish/mouse models of cardiac development.
Taken together, our findings support the notion that congenital heart disease, in particular hLHS, may result from perturbations in cardiac progenitor biology and highlight a key role of cilia in human cardiogenesis.