Understanding LMNA mutation caused endothelial dysfunction using patient iPSC derived endothelial cells

LMNA-related dilated cardiomyopathy (DCM), often clinically referred as “cardiolaminopathy”, is characterized by cardiac ventricular enlargement and dysfunction. Cardiolaminopathy patients present with a severe form of the disease that is often associated with conduction abnormalities and heart failure, accounting for approximately 6-10% of all familial DCM. In contrast to other familial DCM, cardiolaminopathy patients demonstrate age-related penetrance with usual onset around 40 years of age. Lamins are expressed in all differentiated cells, and it has been hypothesized that cardiolaminopathy could not only be due to abnormally functioning lamins in cardiomyocytes (CMs), but also due to defects in non-myocytes such as endothelial cells (ECs). Despite being expressed in ECs and that mutations in LMNA are known to induce EC dysfunction, little is known about the EC-specific phenotype in cardiolaminopathy.In this study, we explore the molecular mechanisms that underlie cardiolaminopathy by modeling cardiolaminopathy “disease in-a-dish” using patient-specific induced pluripotent stem cells (iPSCs). Furthermore, our study pave way to novel mechanistic insights into the pathological processes of cardiolaminopathy, allowing us to conduct a “clinical-trial in-a-dish” where a drug was identified and validated for clinical use. Importantly, the validated drug when given to cardiolaminopathy patients showed improvement in their clinical phenotype.