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

doi:10.1016/j.celrep.2016.12.040

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

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

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.

Original language	English (US)
Pages (from-to)	571-582
Number of pages	12
Journal	Cell Reports
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2016.12.040
State	Published - Jan 10 2017
Externally published	Yes

Keywords

ARVC
T-tubule
calcium transient
cardiac progenitor
cardiomyocyte
cardiomyopathy
disease modeling
iPS
maturation
neonatal
sarcomere shortening

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2016.12.040

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Cho, G. S., Lee, D. I., Tampakakis, E., Murphy, S., Andersen, P., Uosaki, H., Chelko, S., Chakir, K., Hong, I., Seo, K., Chen, H. S. V., Chen, X., Basso, C., Houser, S. R., Tomaselli, G. F., O'Rourke, B., Judge, D. P., Kass, D. A., & Kwon, C. (2017). Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy. Cell Reports, 18(2), 571-582. https://doi.org/10.1016/j.celrep.2016.12.040

Cho, GS, Lee, DI, Tampakakis, E, Murphy, S, Andersen, P, Uosaki, H, Chelko, S, Chakir, K, Hong, I, Seo, K, Chen, HSV, Chen, X, Basso, C, Houser, SR, Tomaselli, GF, O'Rourke, B, Judge, DP, Kass, DA & Kwon, C 2017, 'Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy', Cell Reports, vol. 18, no. 2, pp. 571-582. https://doi.org/10.1016/j.celrep.2016.12.040

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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.",

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AU - Cho, Gun Sik

AU - Lee, Dong I.

AU - Tampakakis, Emmanouil

AU - Murphy, Sean

AU - Andersen, Peter

AU - Uosaki, Hideki

AU - Chelko, Stephen

AU - Chakir, Khalid

AU - Hong, Ingie

AU - Seo, Kinya

AU - Chen, Huei Sheng Vincent

AU - Chen, Xiongwen

AU - Basso, Cristina

AU - Houser, Steven R.

AU - Tomaselli, Gordon F.

AU - O'Rourke, Brian

AU - Judge, Daniel P.

AU - Kass, David A.

AU - Kwon, Chulan

PY - 2017/1/10

Y1 - 2017/1/10

N2 - 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.

AB - 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.

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KW - T-tubule

KW - calcium transient

KW - cardiac progenitor

KW - cardiomyocyte

KW - cardiomyopathy

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KW - maturation

KW - neonatal

KW - sarcomere shortening

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Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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