CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes

John W. Ostrominski; Ravi Chandra Yada; Noriko Sato; Michael Klein; Ksenia Blinova; Dakshesh Patel; Racquel Valadez; Maryknoll Palisoc; Stefania Pittaluga; Kah Whye Peng; Hong San; Yongshun Lin; Falguni Basuli; Xiang Zhang; Rolf E. Swenson; Mark Haigney; Peter L. Choyke; Jizhong Zou; Manfred Boehm; So Gun Hong; Cynthia E. Dunbar

doi:10.1002/sctm.20-0019

CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes

John W. Ostrominski, Ravi Chandra Yada, Noriko Sato, Michael Klein, Ksenia Blinova, Dakshesh Patel, Racquel Valadez, Maryknoll Palisoc, Stefania Pittaluga, Kah Whye Peng, Hong San, Yongshun Lin, Falguni Basuli, Xiang Zhang, Rolf E. Swenson, Mark Haigney, Peter L. Choyke, Jizhong Zou, Manfred Boehm, So Gun Hong^*Cynthia E. Dunbar^*

^*Corresponding author for this work

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

11 Scopus citations

Abstract

Techniques that enable longitudinal tracking of cell fate after myocardial delivery are imperative for optimizing the efficacy of cell-based cardiac therapies. However, these approaches have been underutilized in preclinical models and clinical trials, and there is considerable demand for site-specific strategies achieving long-term expression of reporter genes compatible with safe noninvasive imaging. In this study, the rhesus sodium/iodide symporter (NIS) gene was incorporated into rhesus macaque induced pluripotent stem cells (RhiPSCs) via CRISPR/Cas9. Cardiomyocytes derived from NIS-RhiPSCs (NIS-RhiPSC-CMs) exhibited overall similar morphological and electrophysiological characteristics compared to parental control RhiPSC-CMs at baseline and with exposure to physiological levels of sodium iodide. Mice were injected intramyocardially with 2 million NIS-RhiPSC-CMs immediately following myocardial infarction, and serial positron emission tomography/computed tomography was performed with ¹⁸F-tetrafluoroborate to monitor transplanted cells in vivo. NIS-RhiPSC-CMs could be detected until study conclusion at 8 to 10 weeks postinjection. This NIS-based molecular imaging platform, with optimal safety and sensitivity characteristics, is primed for translation into large-animal preclinical models and clinical trials.

Original language	English
Pages (from-to)	1203-1217
Number of pages	15
Journal	Stem Cells Translational Medicine
Volume	9
Issue number	10
DOIs	https://doi.org/10.1002/sctm.20-0019
State	Published - 1 Oct 2020
Externally published	Yes

Keywords

CRISPR/Cas9
NIS
PET
cardiomyocytes
electrophysiology
iPSCs
imaging
in vivo tracking
rhesus macaque
sodium iodide symporter

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10.1002/sctm.20-0019

Cite this

Ostrominski, J. W., Yada, R. C., Sato, N., Klein, M., Blinova, K., Patel, D., Valadez, R., Palisoc, M., Pittaluga, S., Peng, K. W., San, H., Lin, Y., Basuli, F., Zhang, X., Swenson, R. E., Haigney, M., Choyke, P. L., Zou, J., Boehm, M., ... Dunbar, C. E. (2020). CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes. Stem Cells Translational Medicine, 9(10), 1203-1217. https://doi.org/10.1002/sctm.20-0019

@article{dcc2442f0bb047889175761e17145ee0,

title = "CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes",

abstract = "Techniques that enable longitudinal tracking of cell fate after myocardial delivery are imperative for optimizing the efficacy of cell-based cardiac therapies. However, these approaches have been underutilized in preclinical models and clinical trials, and there is considerable demand for site-specific strategies achieving long-term expression of reporter genes compatible with safe noninvasive imaging. In this study, the rhesus sodium/iodide symporter (NIS) gene was incorporated into rhesus macaque induced pluripotent stem cells (RhiPSCs) via CRISPR/Cas9. Cardiomyocytes derived from NIS-RhiPSCs (NIS-RhiPSC-CMs) exhibited overall similar morphological and electrophysiological characteristics compared to parental control RhiPSC-CMs at baseline and with exposure to physiological levels of sodium iodide. Mice were injected intramyocardially with 2 million NIS-RhiPSC-CMs immediately following myocardial infarction, and serial positron emission tomography/computed tomography was performed with 18F-tetrafluoroborate to monitor transplanted cells in vivo. NIS-RhiPSC-CMs could be detected until study conclusion at 8 to 10 weeks postinjection. This NIS-based molecular imaging platform, with optimal safety and sensitivity characteristics, is primed for translation into large-animal preclinical models and clinical trials.",

keywords = "CRISPR/Cas9, NIS, PET, cardiomyocytes, electrophysiology, iPSCs, imaging, in vivo tracking, rhesus macaque, sodium iodide symporter",

author = "Ostrominski, {John W.} and Yada, {Ravi Chandra} and Noriko Sato and Michael Klein and Ksenia Blinova and Dakshesh Patel and Racquel Valadez and Maryknoll Palisoc and Stefania Pittaluga and Peng, {Kah Whye} and Hong San and Yongshun Lin and Falguni Basuli and Xiang Zhang and Swenson, {Rolf E.} and Mark Haigney and Choyke, {Peter L.} and Jizhong Zou and Manfred Boehm and Hong, {So Gun} and Dunbar, {Cynthia E.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors. STEM CELLS Translational Medicine published by Wiley Periodicals LLC on behalf of AlphaMed Press.",

year = "2020",

month = oct,

day = "1",

doi = "10.1002/sctm.20-0019",

language = "English",

volume = "9",

pages = "1203--1217",

journal = "Stem Cells Translational Medicine",

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Ostrominski, JW, Yada, RC, Sato, N, Klein, M, Blinova, K, Patel, D, Valadez, R, Palisoc, M, Pittaluga, S, Peng, KW, San, H, Lin, Y, Basuli, F, Zhang, X, Swenson, RE, Haigney, M, Choyke, PL, Zou, J, Boehm, M, Hong, SG & Dunbar, CE 2020, 'CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes', Stem Cells Translational Medicine, vol. 9, no. 10, pp. 1203-1217. https://doi.org/10.1002/sctm.20-0019

CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes. / Ostrominski, John W.; Yada, Ravi Chandra; Sato, Noriko et al.
In: Stem Cells Translational Medicine, Vol. 9, No. 10, 01.10.2020, p. 1203-1217.

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

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T1 - CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes

AU - Ostrominski, John W.

AU - Yada, Ravi Chandra

AU - Sato, Noriko

AU - Klein, Michael

AU - Blinova, Ksenia

AU - Patel, Dakshesh

AU - Valadez, Racquel

AU - Palisoc, Maryknoll

AU - Pittaluga, Stefania

AU - Peng, Kah Whye

AU - San, Hong

AU - Lin, Yongshun

AU - Basuli, Falguni

AU - Zhang, Xiang

AU - Swenson, Rolf E.

AU - Haigney, Mark

AU - Choyke, Peter L.

AU - Zou, Jizhong

AU - Boehm, Manfred

AU - Hong, So Gun

AU - Dunbar, Cynthia E.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Techniques that enable longitudinal tracking of cell fate after myocardial delivery are imperative for optimizing the efficacy of cell-based cardiac therapies. However, these approaches have been underutilized in preclinical models and clinical trials, and there is considerable demand for site-specific strategies achieving long-term expression of reporter genes compatible with safe noninvasive imaging. In this study, the rhesus sodium/iodide symporter (NIS) gene was incorporated into rhesus macaque induced pluripotent stem cells (RhiPSCs) via CRISPR/Cas9. Cardiomyocytes derived from NIS-RhiPSCs (NIS-RhiPSC-CMs) exhibited overall similar morphological and electrophysiological characteristics compared to parental control RhiPSC-CMs at baseline and with exposure to physiological levels of sodium iodide. Mice were injected intramyocardially with 2 million NIS-RhiPSC-CMs immediately following myocardial infarction, and serial positron emission tomography/computed tomography was performed with 18F-tetrafluoroborate to monitor transplanted cells in vivo. NIS-RhiPSC-CMs could be detected until study conclusion at 8 to 10 weeks postinjection. This NIS-based molecular imaging platform, with optimal safety and sensitivity characteristics, is primed for translation into large-animal preclinical models and clinical trials.

AB - Techniques that enable longitudinal tracking of cell fate after myocardial delivery are imperative for optimizing the efficacy of cell-based cardiac therapies. However, these approaches have been underutilized in preclinical models and clinical trials, and there is considerable demand for site-specific strategies achieving long-term expression of reporter genes compatible with safe noninvasive imaging. In this study, the rhesus sodium/iodide symporter (NIS) gene was incorporated into rhesus macaque induced pluripotent stem cells (RhiPSCs) via CRISPR/Cas9. Cardiomyocytes derived from NIS-RhiPSCs (NIS-RhiPSC-CMs) exhibited overall similar morphological and electrophysiological characteristics compared to parental control RhiPSC-CMs at baseline and with exposure to physiological levels of sodium iodide. Mice were injected intramyocardially with 2 million NIS-RhiPSC-CMs immediately following myocardial infarction, and serial positron emission tomography/computed tomography was performed with 18F-tetrafluoroborate to monitor transplanted cells in vivo. NIS-RhiPSC-CMs could be detected until study conclusion at 8 to 10 weeks postinjection. This NIS-based molecular imaging platform, with optimal safety and sensitivity characteristics, is primed for translation into large-animal preclinical models and clinical trials.

KW - CRISPR/Cas9

KW - NIS

KW - PET

KW - cardiomyocytes

KW - electrophysiology

KW - iPSCs

KW - imaging

KW - in vivo tracking

KW - rhesus macaque

KW - sodium iodide symporter

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U2 - 10.1002/sctm.20-0019

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M3 - Article

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SN - 2157-6564

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JO - Stem Cells Translational Medicine

JF - Stem Cells Translational Medicine

IS - 10

ER -

CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes

Abstract

Keywords

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