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Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation.
Wauchop, Marianne; Rafatian, Naimeh; Zhao, Yimu; Chen, Wenliang; Gagliardi, Mark; Massé, Stéphane; Cox, Brian J; Lai, Patrick; Liang, Timothy; Landau, Shira; Protze, Stephanie; Gao, Xiao Dong; Wang, Erika Yan; Tung, Kelvin Chan; Laksman, Zachary; Lu, Rick Xing Ze; Keller, Gordon; Nanthakumar, Kumaraswamy; Radisic, Milica; Backx, Peter H.
Affiliation
  • Wauchop M; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Rafatian N; Division of Cardiology and Peter Munk Cardiac Center, University Health Network, Toronto, ON, M5G 1L7, Canada.
  • Zhao Y; Toronto General Hospital Research Institute, Toronto, ON, M5G 2C4, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
  • Chen W; Division of Cardiology and Peter Munk Cardiac Center, University Health Network, Toronto, ON, M5G 1L7, Canada; Department of Biology, York University, Toronto, ON, M3J 1P3, Canada.
  • Gagliardi M; McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada.
  • Massé S; Division of Cardiology and Peter Munk Cardiac Center, University Health Network, Toronto, ON, M5G 1L7, Canada; Toronto General Hospital Research Institute, Toronto, ON, M5G 2C4, Canada; The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, ON, M5G 2C4, Canada
  • Cox BJ; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada; Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Lai P; Division of Cardiology and Peter Munk Cardiac Center, University Health Network, Toronto, ON, M5G 1L7, Canada; Toronto General Hospital Research Institute, Toronto, ON, M5G 2C4, Canada; The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, ON, M5G 2C4, Canada
  • Liang T; Division of Cardiology and Peter Munk Cardiac Center, University Health Network, Toronto, ON, M5G 1L7, Canada; Toronto General Hospital Research Institute, Toronto, ON, M5G 2C4, Canada; The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, ON, M5G 2C4, Canada
  • Landau S; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
  • Protze S; McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Gao XD; Department of Biology, York University, Toronto, ON, M3J 1P3, Canada.
  • Wang EY; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
  • Tung KC; McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada.
  • Laksman Z; Department of Medicine, University of British Columbia, Vancouver, BC, V6E 1M7, Canada.
  • Lu RXZ; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
  • Keller G; McEwen Stem Cell Institute, University Health Network, Toronto, ON, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
  • Nanthakumar K; Division of Cardiology and Peter Munk Cardiac Center, University Health Network, Toronto, ON, M5G 1L7, Canada; Toronto General Hospital Research Institute, Toronto, ON, M5G 2C4, Canada; The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, ON, M5G 2C4, Canada
  • Radisic M; Toronto General Hospital Research Institute, Toronto, ON, M5G 2C4, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada, M5S 3E5. Electronic address: m.ra
  • Backx PH; Division of Cardiology and Peter Munk Cardiac Center, University Health Network, Toronto, ON, M5G 1L7, Canada; Department of Biology, York University, Toronto, ON, M3J 1P3, Canada; Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
Biomaterials ; 301: 122255, 2023 10.
Article de En | MEDLINE | ID: mdl-37651922
ABSTRACT
To better understand sodium channel (SCN5A)-related cardiomyopathies, we generated ventricular cardiomyocytes from induced pluripotent stem cells obtained from a dilated cardiomyopathy patient harbouring the R222Q mutation, which is only expressed in adult SCN5A isoforms. Because the adult SCN5A isoform was poorly expressed, without functional differences between R222Q and control in both embryoid bodies and cell sheet preparations (cultured for 29-35 days), we created heart-on-a-chip biowires which promote myocardial maturation. Indeed, biowires expressed primarily adult SCN5A with R222Q preparations displaying (arrhythmogenic) short action potentials, altered Na+ channel biophysical properties and lower contractility compared to corrected controls. Comprehensive RNA sequencing revealed differential gene regulation between R222Q and control biowires in cellular pathways related to sarcoplasmic reticulum and dystroglycan complex as well as biological processes related to calcium ion regulation and action potential. Additionally, R222Q biowires had marked reductions in actin expression accompanied by profound sarcoplasmic disarray, without differences in cell composition (fibroblast, endothelial cells, and cardiomyocytes) compared to corrected biowires. In conclusion, we demonstrate that in addition to altering cardiac electrophysiology and Na+ current, the R222Q mutation also causes profound sarcomere disruptions and mechanical destabilization. Possible mechanisms for these observations are discussed.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Cardiomyopathie dilatée / Cellules souches pluripotentes induites Limites: Adult / Humans Langue: En Journal: Biomaterials Année: 2023 Type de document: Article Pays d'affiliation: Canada
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Cardiomyopathie dilatée / Cellules souches pluripotentes induites Limites: Adult / Humans Langue: En Journal: Biomaterials Année: 2023 Type de document: Article Pays d'affiliation: Canada