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

Gustavo Monnerat; Tais Hanae Kasai-Brunswick; Karina Dutra Asensi; Danubia Silva Dos Santos; Raiana Andrade Quintanilha Barbosa; Fernanda Cristina Paccola Mesquita; Joao Paulo Calvancanti Albuquerque; Pires Ferreira Raphaela; Camila Wendt; Kildare Miranda; Gilberto Barbosa Domont; Fábio César Sousa Nogueira; Adriana Bastos Carvalho; Antonio Carlos Campos de Carvalho

doi:10.3389/fphys.2022.1007418

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

Front Physiol. 2022 Nov 23:13:1007418. doi: 10.3389/fphys.2022.1007418. eCollection 2022.

Authors

Gustavo Monnerat^{1

2}, Tais Hanae Kasai-Brunswick^{1

3}, Karina Dutra Asensi¹, Danubia Silva Dos Santos¹, Raiana Andrade Quintanilha Barbosa¹, Fernanda Cristina Paccola Mesquita¹, Joao Paulo Calvancanti Albuquerque¹, Pires Ferreira Raphaela¹, Camila Wendt¹, Kildare Miranda¹, Gilberto Barbosa Domont⁴, Fábio César Sousa Nogueira^{2

4}, Adriana Bastos Carvalho¹, Antonio Carlos Campos de Carvalho^{1

5}

Affiliations

¹ Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
² Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
³ National Center of Structural Biology and Bioimaging, CENABIO, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁴ Proteomic Unit, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁵ National Science and Technology Institute in Regenerative Medicine, Rio de Janeiro, Brazil.

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.

Keywords: aging; cardiology; mass spectrometery (MS); metabolism; pluripotent stem cell (PSC); progeria; proteomics.

Copyright © 2022 Monnerat, Kasai-Brunswick, Asensi, Silva dos Santos, Barbosa, Cristina Paccola Mesquita, Calvancanti Albuquerque, Raphaela, Wendt, Miranda, Domont, Nogueira, Bastos Carvalho and Campos de Carvalho.