title: Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy.
abstract: 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.
  
  
  
  We found that, in ACM patients' explanted heart sections, cells actively differentiating into adipocytes are of mesenchymal 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, via Parea 4, Milan 20138, Italy esommariva@ccfm.it.
authors.forename: E
authors.initials: E
authors.lastname: Sommariva
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, via Parea 4, Milan 20138, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Brambilla
authors.affiliation: Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Carbucicchio
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, via Parea 4, Milan 20138, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Gambini
authors.affiliation: Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy - Affiliated Institute of the University of Lübeck, Lübeck, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Meraviglia
authors.affiliation: Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Dello Russo
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, via Parea 4, Milan 20138, Italy.
authors.forename: F M
authors.initials: FM
authors.lastname: Farina
authors.affiliation: Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Casella
authors.affiliation: Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Catto
authors.affiliation: Department of Cardiovascular Imaging, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pontone
authors.affiliation: Immunology and Functional Genomics Unit, Centro Cardiologico Monzino IRCCS, Milan, Italy Electrical Computer and Biomedical Engineering, Università degli Studi di Pavia, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Chiesa
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, via Parea 4, Milan 20138, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Stadiotti
authors.affiliation: Tissue Bank of Veneto Region, Ca' Foncello Hospital, Treviso, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cogliati
authors.affiliation: Tissue Bank of Veneto Region, Ca' Foncello Hospital, Treviso, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Paolin
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, via Parea 4, Milan 20138, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Ouali Alami
authors.affiliation: Department of Radiological, Oncological and Pathologic Sciences, La Sapienza University, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Preziuso
authors.affiliation: Department of Radiological, Oncological and Pathologic Sciences, La Sapienza University, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: d'Amati
authors.affiliation: Immunology and Functional Genomics Unit, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: G I
authors.initials: GI
authors.lastname: Colombo
authors.affiliation: Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy - Affiliated Institute of the University of Lübeck, Lübeck, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rossini
authors.affiliation: Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Rome, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Capogrossi
authors.affiliation: Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Tondo
authors.affiliation: Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, via Parea 4, Milan 20138, Italy Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pompilio
mesh_terms: D017667:Adipocytes / Q000473:pathology*; D050156:Adipogenesis / Q000502:physiology; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D008875:Middle Aged; D051191:Plakophilins / Q000378:metabolism; D051185:gamma Catenin / Q000378:metabolism
chemical_list: D051191:Plakophilins; D051185:gamma Catenin
keywords: Adipogenesis; Arrhythmogenic cardiomyopathy; Fibrofatty substitution; Mesenchymal stromal cells; Plakoglobin; Plakophilin2