Abstract 503: Modeling Premature Cardiac Aging by Induced Pluripotent Stem Cell From a Patient With Hutchinson-Gilford Progeria Syndrome

Abstract

Background: Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder characterized by accelerated aging and high incidence of cardiovascular complications and metabolic alterations. However, the underlying mechanisms of this syndrome are not fully understood. Methods and Results: This study modelled HGPS using cardiomyocytes generated from induced pluripotent stem cells (iPSc) derived from a patient affected by the syndrome, characterizing the molecular and biophysical alterations found in cardiomyocytes obtained from three distinct differentiation protocols run in parallel with a control iPSc. Electrophysiology recordings were performed with intracellular microelectrodes and the Progeria cardiomyocytes fired action potentials similar to those from control iPSc-derived cardiomyocytes. High resolution respirometry performed on Oroboros system in isolated cardiomyocytes showed that Progeria cardiomyocytes have a tendency to decrease the oxygen consumption under basal condition and after FCCP, when compared to control cardiomyocytes (P=0.06). Furthermore, HGPS cardiomyocytes produced less ROS under basal and after 100uM Hydrogen peroxide treatment. However, mitotracker analysis shows no difference on mitochondrial content. Electron tomography and 3D reconstruction analysis suggest structural abnormalities in the mitochondria of Progeria cardiomyocytes. Proteomics analysis, performed with Liquid Chromatography tandem mass spectrometry (LC-MS/MS) in a high-resolution system (Q-Exactive Plus, Thermo Fischer), shows differential protein expression between Progeria (183 unique proteins) and Control (225 unique proteins) IPSc - derived cardiomyocytes. Conclusions: Our work demonstrate that iPSc- derived cardiomyocytes from Progeria patients have significant alterations in cellular respiration and protein expression.