Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy

E. Sommariva, S. Brambilla, C. Carbucicchio, E. Gambini, V. Meraviglia, A. Dello Russo, F. M. Farina, M. Casella, Valentina Ilaria Maria Catto, G. Pontone, M. Chiesa, Ilaria Stadiotti, E. Cogliati, A. Paolin, N. Ouali Alami, C. Preziuso, G. D'Amati, G. I. Colombo, A. Rossini, M. C. CapogrossiC. Tondo, G. Pompilio

Research output: Contribution to journalArticle

Abstract

Aim: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder mainly due to mutations in desmosomal genes, characterized by progressive fibro-adipose replacement of the myocardium, arrhythmias, and sudden death. It is still unclear which cell type is responsible for fibro-adipose substitution and which molecular mechanisms lead to this structural change. Cardiac mesenchymal stromal cells (C-MSC) are the most abundant cells in the heart, with propensity to differentiate into several cell types, including adipocytes, and their role in ACM is unknown. The aim of the present study was to investigate whether C-MSC contributed to excess adipocytes in patients with ACM. Methods: We found that, in ACM patients' explanted heart sections, cells actively differentiating into adipocytes are of mes-and results: enchymal origin. Therefore, we isolated C-MSC from endomyocardial biopsies of ACM and from not affected by arrhythmogenic cardiomyopathy (NON-ACM) (control) patients. We found that both ACM and control C-MSC express desmosomal genes, with ACM C-MSC showing lower expression of plakophilin (PKP2) protein vs. controls. Arrhythmogenic cardiomyopathy C-MSC cultured in adipogenic medium accumulated more lipid droplets than controls. Accordingly, the expression of adipogenic genes was higher in ACM vs. NON-ACM C-MSC, while expression of cell cycle and anti-adipogenic genes was lower. Both lipid accumulation and transcription reprogramming were dependent on PKP2 deficiency. Conclusions: Cardiac mesenchymal stromal cells contribute to the adipogenic substitution observed in ACM patients' hearts. Moreover, C-MSC from ACM patients recapitulate the features of ACM adipogenesis, representing a novel, scalable, patient-specific in vitro tool for future mechanistic studies.

Original languageEnglish
Pages (from-to)1835-1846
Number of pages12
JournalEuropean Heart Journal
Volume57
Issue number23
DOIs
Publication statusPublished - 2016

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Keywords

  • Adipogenesis
  • Arrhythmogenic cardiomyopathy
  • Fibrofatty substitution
  • Mesenchymal stromal cells
  • Plakoglobin
  • Plakophilin2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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