Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy.
The phenotypic hallmark of arrhythmogenic right ventricular cardiomyopathy, a genetic disease of desmosomal proteins, is fibroadipocytic replacement of the right ventricle. Cellular origin of excess adipocytes, the responsible mechanism(s) and the basis for predominant involvement of the right ventricle are unknown. We generated 3 sets of lineage tracer mice regulated by cardiac lineage promoters alpha-myosin heavy chain (alphaMyHC), Nkx2.5, or Mef2C. We conditionally expressed the reporter enhanced yellow fluorescent protein while concomitantly deleting the desmosomal protein desmoplakin in cardiac myocyte lineages using the Cre-LoxP technique. Lineage tracer mice showed excess fibroadiposis and increased numbers of adipocytes in the hearts. Few adipocytes in the hearts of alphaMyHC-regulated lineage tracer mice, but the majority of adipocytes in the hearts of Nkx2.5- and Mef2C-regulated lineage tracer mice, expressed enhanced yellow fluorescent protein. In addition, rare cells coexpressed adipogenic transcription factors and the second heart field markers Isl1 and Mef2C in the lineage tracer mouse hearts and in human myocardium from patients with arrhythmogenic right ventricular cardiomyopathy. To delineate the responsible mechanism, we generated transgenic mice expressing desmosomal protein plakoglobin in myocyte lineages. Transgene plakoglobin translocated to nucleus, detected by immunoblotting and immunofluorescence staining and coimmunoprecipitated with Tcf7l2, a canonical Wnt signaling transcription factor. Expression levels of canonical Wnt/Tcf7l2 targets bone morphogenetic protein 7 and Wnt5b, which promote adipogenesis, were increased and expression level of connective tissue growth factor, an inhibitor of adipogenesis, was decreased. We conclude adipocytes in arrhythmogenic right ventricular cardiomyopathy originate from the second heart field cardiac progenitors, which switch to an adipogenic fate because of suppressed canonical Wnt signaling by nuclear plakoglobin.
Center for Cardiovascular Genetics, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center, 6770 Bertner Street, Houston, TX 77030, USA.
Raffaella
R
Lombardi
Jinjiang
J
Dong
Gabriela
G
Rodriguez
Achim
A
Bell
Tack Ki
TK
Leung
Robert J
RJ
Schwartz
James T
JT
Willerson
Ramon
R
Brugada
Ali J
AJ
Marian
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D050156:Adipogenesis / Q000235:genetics*; D000328:Adult; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics*; D051180:Desmoplakins / Q000172:deficiency; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D005355:Fibrosis; D005838:Genotype; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins; D026161:MADS Domain Proteins / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism
D055419:Bone Morphogenetic Protein 7; D051180:Desmoplakins; C495295:Dsp protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C495293:Jup protein, mouse; D060850:LIM-Homeodomain Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; C484469:Nkx2-5 protein, mouse; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; C468567:Wnt5b protein, mouse; D051185:gamma Catenin; C063843:insulin gene enhancer binding protein Isl-1; D018995:Myosin Heavy Chains