Modelling premature cardiac aging with induced pluripotent stem cells from a hutchinson-gilford Progeria Syndrome patient

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that causes accelerated aging and a high risk of cardiovascular complications. However, the underlying mechanisms of cardiac complications of this syndrome are not fully understood. This study modeled HGPS using cardiomyocytes (CM) derived from induced pluripotent stem cells (iPSC) derived from a patient with HGPS and characterized the biophysical, morphological, and molecular changes found in these CM compared to CM derived from a healthy donor. Electrophysiological recordings suggest that the HGPS-CM was functional and had normal electrophysiological properties. Electron tomography showed nuclear morphology alteration, and the 3D reconstruction of electron tomography images suggests structural abnormalities in HGPS-CM mitochondria, however, there was no difference in mitochondrial content as measured by Mitotracker. Immunofluorescence indicates nuclear morphological alteration and confirms the presence of Troponin T. Telomere length was measured using qRT-PCR, and no difference was found in the CM from HGPS when compared to the control. Proteomic analysis was carried out in a high-resolution system using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). The proteomics data show distinct group separations and protein expression differences between HGPS and control-CM, highlighting changes in ribosomal, TCA cycle, and amino acid biosynthesis, among other modifications. Our findings show that iPSC-derived cardiomyocytes from a Progeria Syndrome patient have significant changes in mitochondrial morphology and protein expression, implying novel mechanisms underlying premature cardiac aging.

Aging Triggers Mitochondrial Dysfunction in Mice

“…Interestingly, a recent study using induced pluripotent stem cell-derived cardiomyocytes from a patient with Hutchinson–Gilford Progeria Syndrome found that premature aging is also associated with mitochondrial alterations in cardiac cells. The study discovered structural abnormalities in mitochondria, while high-resolution proteomics data revealed significant changes in protein expression related to the tricarboxylic acid cycle [ 26 ].…”

A longevity-specific bank of induced pluripotent stem cells from centenarians and their offspring

“…This potential utility of iPSCs in aging research has recently been highlighted as a platform for both longevity studies as well as drug discovery 23 . EL iPSCs also provide a complement for studies performed on aging disease-specific lines, such as those derived from patients with Progeria 24,25 , given their potential in understanding mechanisms that embolden resiliency and resistance to accelerated aging-related disease.…”

“…disease-specific lines, such as those derived from patients with Progeria 24,25 , given their potential in understanding mechanisms that embolden resiliency and resistance to accelerated aging-related disease. Here, we report a novel bank of longevity-specific peripheral blood mononuclear cells (PBMCs) and resultant iPSCs from subjects with EL.…”