title: iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy.
abstract: Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and its pathogenesis has been associated with the developmental defect of the embryonic myocardium. We show that patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from LVNC patients carrying a mutation in the cardiac transcription factor TBX20 recapitulate a key aspect of the pathological phenotype at the single-cell level and this was associated with perturbed transforming growth factor beta (TGF-β) signalling. LVNC iPSC-CMs have decreased proliferative capacity due to abnormal activation of TGF-β signalling. TBX20 regulates the expression of TGF-β signalling modifiers including one known to be a genetic cause of LVNC, PRDM16, and genome editing of PRDM16 caused proliferation defects in iPSC-CMs. Inhibition of TGF-β signalling and genome correction of the TBX20 mutation were sufficient to reverse the disease phenotype. Our study demonstrates that iPSC-CMs are a useful tool for the exploration of pathological mechanisms underlying poorly understood cardiomyopathies including LVNC.
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kodo
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Sang-Ging
authors.initials: SG
authors.lastname: Ong
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Fereshteh
authors.initials: F
authors.lastname: Jahanbani
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.|Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Vittavat
authors.initials: V
authors.lastname: Termglinchan
authors.affiliation: Department of Pediatrics, University of Toyama, Toyama-shi, Toyama 930-8555, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hirono
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kolsoum
authors.initials: K
authors.lastname: InanlooRahatloo
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.|Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Antje D
authors.initials: AD
authors.lastname: Ebert
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Shukla
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Oscar J
authors.identifier: 0000-0002-9991-400X
authors.initials: OJ
authors.lastname: Abilez
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.|Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Churko
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.|Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Gwanghyun
authors.initials: G
authors.lastname: Jung
authors.affiliation: Department of Pediatrics, University of Toyama, Toyama-shi, Toyama 930-8555, Japan.
authors.forename: Fukiko
authors.initials: F
authors.lastname: Ichida
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wu
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, California 94305, USA.|Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D020825:T-Box Domain Proteins; C420984:TBX20 protein, human; D016212:Transforming Growth Factor beta