title: Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy.
abstract: 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.
authors.affiliation: 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.
authors.forename: Gun-Sik
authors.initials: GS
authors.lastname: Cho
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Dong I
authors.initials: DI
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Tampakakis
authors.affiliation: 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.
authors.forename: Sean
authors.initials: S
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: 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.
authors.forename: Hideki
authors.initials: H
authors.lastname: Uosaki
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chelko
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Chakir
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ingie
authors.initials: I
authors.lastname: Hong
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kinya
authors.initials: K
authors.lastname: Seo
authors.affiliation: Del E. Webb Neuroscience, Aging & Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Huei-Sheng Vincent
authors.initials: HV
authors.lastname: Chen
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: dkass@jhmi.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: 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. Electronic address: ckwon13@jhmi.edu.
authors.forename: Chulan
authors.initials: C
authors.lastname: Kwon
mesh_terms: D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002454:Cell Differentiation; D048430:Cell Shape; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000648:ultrastructure; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology*; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology*; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D033581:Stem Cell Transplantation
chemical_list: D002118:Calcium
keywords: ARVC; T-tubule; calcium transient; cardiac progenitor; cardiomyocyte; cardiomyopathy; disease modeling; iPS; maturation; neonatal; sarcomere shortening