Cho Gun-Sik, Lee Dong I, Tampakakis Emmanouil, Murphy Sean, Andersen Peter, Uosaki Hideki, Chelko Stephen, Chakir Khalid, Hong Ingie, Seo Kinya, Chen Huei-Sheng Vincent, Chen Xiongwen, Basso Cristina, Houser Steven R, Tomaselli Gordon F, O'Rourke Brian, Judge Daniel P, Kass David A, Kwon Chulan
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.
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Rep. 2017 Jan 10;18(2):571-582. doi: 10.1016/j.celrep.2016.12.040.
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.
多能干细胞（PSC）为疾病建模和个性化医疗提供了前所未有的机遇。然而，PSC衍生的细胞表现出胎儿样特征，在培养皿中仍不成熟。这已成为它们应用于晚发性疾病的主要障碍。我们之前表明，长期培养的PSC衍生心肌细胞（PSC-CM）存在新生儿期停滞。在此，我们证明，将PSC-CM移植到新生心脏中时，它们会成熟为成体心肌细胞。移植到大鼠体内一个月内，PSC-CM在形态、结构和功能上变得与成体心肌细胞相似。单细胞RNA测序分析进一步支持了这种相似性。此外，这种体内成熟使患者来源的PSC-CM能够揭示主要在成人中表现的致心律失常性右室心肌病的疾病表型。这项研究为理解人类心肌细胞成熟和发病机制奠定了基础，并且有助于基于PSC的成人心脏病建模。
