title: Mouse P2Y4Nucleotide Receptor Is a Negative Regulator of Cardiac Adipose-Derived Stem Cell Differentiation and Cardiac Fat Formation.
abstract: Cardiac adipose tissue-derived stem cells (cASCs) have the ability to differentiate into multiple cell lineages giving them a high potential for use in regenerative medicine. Cardiac fat tissue still raises many unsolved questions related to its formation and features. P2Y nucleotide receptors have already been described as regulators of differentiation of bone-marrow derived stem cells, but remain poorly investigated in cASCs. We defined, in this study, the P2Y4nucleotide receptor as a negative regulator of cardiac fat formation and cASC adipogenic differentiation. Higher expression of P2Y4receptor in cardiac fat tissue was observed compared to other adipose tissues. P2Y4-null mice displayed a higher mass of cardiac adipose tissue specifically. We therefore examined the role of P2Y4receptor in cASC adipogenic differentiation. An inhibitory effect of uridine 5'-triphosphate (UTP), ligand of P2Y4, was observed on the maturation state of differentiated cASCs, and on the expression of adipogenesis-linked genes and adiponectin, a cardioprotective adipokine. Higher adiponectin secretion by P2Y4-null adipocytes could be linked with cardioprotection previously observed in the heart of P2Y4-null ischemic mice. We realized here left anterior descending artery ligation on simple and double-knockout mice for P2Y4and adiponectin. No cardioprotective effect of P2Y4loss was observed in the absence of adiponectin secretion. In addition, P2Y4loss was correlated with higher expression of UCP-1 (uncoupling protein-1) and CD137, two markers of brown/beige cardiac adipocytes. Our data highlight the P2Y4receptor as an inhibitor of cardiac fat formation and cASC adipogenic differentiation, and as a potential therapeutic target in the regulation of cardioprotective function of cardiac fat.
authors.affiliation: 1 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Brussels, Belgium .
authors.forename: Anne
authors.initials: A
authors.lastname: Lemaire
authors.affiliation: 1 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Brussels, Belgium .
authors.forename: Marion
authors.initials: M
authors.lastname: Vanorlé
authors.affiliation: 1 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Brussels, Belgium .
authors.forename: Michael
authors.initials: M
authors.lastname: Horckmans
authors.affiliation: 1 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Brussels, Belgium .
authors.forename: Larissa
authors.initials: L
authors.lastname: di Pietrantonio
authors.affiliation: 1 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Brussels, Belgium .
authors.forename: Sophie
authors.initials: S
authors.lastname: Clouet
authors.affiliation: 2 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Gosselies, Belgium .
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.affiliation: 1 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Brussels, Belgium .|3 Department of Laboratory Medicine, Erasme Hospital, Université Libre de Bruxelles , Brussels, Belgium .
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.affiliation: 1 Institute of Interdisciplinary Research (IRIBHM) , Université Libre de Bruxelles, Brussels, Belgium .
authors.forename: Didier
authors.initials: D
authors.lastname: Communi
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology*; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D005260:Female; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000166:cytology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D052242:Adiponectin; D015415:Biomarkers; D002316:Cardiotonic Agents; D018048:Receptors, Purinergic P2; C104749:purinoceptor P2Y4; D014544:Uridine Triphosphate
keywords: P2Y receptors; adipogenesis; adipose stem cells; cardiac; differentiation; extracellular nucleotides