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Modeling congenital heart disease (CHD) in ISL1+ cardiovascular progenitors from patient-specific iPS cells

Final Report Summary - CHD-IPS (Modeling congenital heart disease (CHD) in ISL1+ cardiovascular progenitors from patient-specific iPS cells)

Congenital heart disease (CHD) is the most common human birth defect and causes a huge burden on patients, their families and health care professionals as well as our society as a whole. However, the molecular basis of the complex malformation of the heart is only poorly understood. Insights into these mechanisms could initiate development of new treatment strategies as well as improve diagnosis of affected individuals, maybe even in utero. We started investigating the hypothesis that distinct heart precursor cell populations are altered in their developmental abilities and are therefore unable to contribute to the developing heart as they normally do. This new approach on deciphering developmental maladies not as a defect in a single gene but as a problem in a certain cell lineage has shed new light on our understanding of CHDs as a whole. By combining genetically manipulated mouse ESCs and in vivo mouse models we uncovered a novel mechanism by which the LIM-Homeodomain transcription factor Isl1 and its transcriptional complex coordinate cardiac progenitor cell differentiation and SHF development. This data provides exciting novel insights into the molecular machinery that orchestrates chromatin organization and coordinated gene expression in three-dimensional space during cardiogenesis.
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.