Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy
Gun-Sik Cho,
Dong I. Lee,
Emmanouil Tampakakis,
Sean Murphy,
Peter Andersen,
Hideki Uosaki,
Stephen Chelko,
Khalid Chakir,
Ingie Hong,
Kinya Seo,
Huei-Sheng Vincent Chen,
Xiongwen Chen,
Cristina Basso,
Steven R. Houser,
Gordon F. Tomaselli,
Brian O’Rourke,
Daniel P. Judge,
David A. Kass,
Chulan Kwon
Affiliations
Gun-Sik Cho
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Dong I. Lee
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Emmanouil Tampakakis
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Sean Murphy
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Peter Andersen
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Hideki Uosaki
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Stephen Chelko
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Khalid Chakir
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ingie Hong
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Kinya Seo
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Huei-Sheng Vincent Chen
Del E. Webb Neuroscience, Aging & Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA
Xiongwen Chen
Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA
Cristina Basso
Department of Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140 USA; Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua, Padova, Italy
Steven R. Houser
Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA
Gordon F. Tomaselli
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Brian O’Rourke
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Daniel P. Judge
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
David A. Kass
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Chulan Kwon
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Summary: Pluripotent stem cells (PSCs) offer unprecedented opportunities for disease modeling and personalized medicine. However, PSC-derived cells exhibit fetal-like characteristics and remain immature in a dish. This has emerged as a major obstacle for their application for late-onset diseases. We previously showed that there is a neonatal arrest of long-term cultured PSC-derived cardiomyocytes (PSC-CMs). Here, we demonstrate that PSC-CMs mature into adult CMs when transplanted into neonatal hearts. PSC-CMs became similar to adult CMs in morphology, structure, and function within a month of transplantation into rats. The similarity was further supported by single-cell RNA-sequencing analysis. Moreover, this in vivo maturation allowed patient-derived PSC-CMs to reveal the disease phenotype of arrhythmogenic right ventricular cardiomyopathy, which manifests predominantly in adults. This study lays a foundation for understanding human CM maturation and pathogenesis and can be instrumental in PSC-based modeling of adult heart diseases. : Pluripotent stem cell (PSC)-derived cells remain fetal like, and this has become a major impediment to modeling adult diseases. Cho et al. find that PSC-derived cardiomyocytes mature into adult cardiomyocytes when transplanted into neonatal rat hearts. This method can serve as a tool to understand maturation and pathogenesis in human cardiomyocytes. Keywords: cardiomyocyte, maturation, iPS, cardiac progenitor, neonatal, disease modeling, cardiomyopathy, ARVC, T-tubule, calcium transient, sarcomere shortening
