Disease characterization using LQTS-specific induced pluripotent stem cells

Toru Egashira; Shinsuke Yuasa; Tomoyuki Suzuki; Yoshiyasu Aizawa; Hiroyuki Yamakawa; Tomohiro Matsuhashi; Yohei Ohno; Shugo Tohyama; Shinichiro Okata; Tomohisa Seki; Yusuke Kuroda; Kojiro Yae; Hisayuki Hashimoto; Tomofumi Tanaka; Fumiyuki Hattori; Toshiaki Sato; Shunichiro Miyoshi; Seiji Takatsuki; Mitsushige Murata; Junko Kurokawa; Tetsushi Furukawa; Naomasa Makita; Takeshi Aiba; Wataru Shimizu; Minoru Horie; Kaichiro Kamiya; Itsuo Kodama; Satoshi Ogawa; Keiichi Fukuda

doi:10.1093/cvr/cvs206

Disease characterization using LQTS-specific induced pluripotent stem cells

Toru Egashira, Shinsuke Yuasa, Tomoyuki Suzuki, Yoshiyasu Aizawa, Hiroyuki Yamakawa, Tomohiro Matsuhashi, Yohei Ohno, Shugo Tohyama, Shinichiro Okata, Tomohisa Seki, Yusuke Kuroda, Kojiro Yae, Hisayuki Hashimoto, Tomofumi Tanaka, Fumiyuki Hattori, Toshiaki Sato, Shunichiro Miyoshi, Seiji Takatsuki, Mitsushige Murata, Junko KurokawaTetsushi Furukawa, Naomasa Makita, Takeshi Aiba, Wataru Shimizu, Minoru Horie, Kaichiro Kamiya, Itsuo Kodama, Satoshi Ogawa, Keiichi Fukuda

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

139 Citations (Scopus)

Abstract

Aims Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). Methods and resultsWe reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. ConclusionsThis study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

Original language	English
Pages (from-to)	419-429
Number of pages	11
Journal	Cardiovascular Research
Volume	95
Issue number	4
DOIs	https://doi.org/10.1093/cvr/cvs206
Publication status	Published - 2012 Sept 1

Keywords

Cardiomyocytes
Drug examination
Long QT syndrome
Personalized medicine
iPS cells

ASJC Scopus subject areas

Medicine(all)

UN SDGs

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

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Egashira, T., Yuasa, S., Suzuki, T., Aizawa, Y., Yamakawa, H., Matsuhashi, T., Ohno, Y., Tohyama, S., Okata, S., Seki, T., Kuroda, Y., Yae, K., Hashimoto, H., Tanaka, T., Hattori, F., Sato, T., Miyoshi, S., Takatsuki, S., Murata, M., ... Fukuda, K. (2012). Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovascular Research, 95(4), 419-429. https://doi.org/10.1093/cvr/cvs206

Egashira, T, Yuasa, S, Suzuki, T, Aizawa, Y, Yamakawa, H, Matsuhashi, T, Ohno, Y, Tohyama, S, Okata, S, Seki, T, Kuroda, Y, Yae, K, Hashimoto, H, Tanaka, T, Hattori, F, Sato, T, Miyoshi, S, Takatsuki, S, Murata, M, Kurokawa, J, Furukawa, T, Makita, N, Aiba, T, Shimizu, W, Horie, M, Kamiya, K, Kodama, I, Ogawa, S & Fukuda, K 2012, 'Disease characterization using LQTS-specific induced pluripotent stem cells', Cardiovascular Research, vol. 95, no. 4, pp. 419-429. https://doi.org/10.1093/cvr/cvs206

@article{02842c81d50946a1a24b398f31a741b3,

title = "Disease characterization using LQTS-specific induced pluripotent stem cells",

abstract = "Aims Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). Methods and resultsWe reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. ConclusionsThis study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.",

keywords = "Cardiomyocytes, Drug examination, Long QT syndrome, Personalized medicine, iPS cells",

author = "Toru Egashira and Shinsuke Yuasa and Tomoyuki Suzuki and Yoshiyasu Aizawa and Hiroyuki Yamakawa and Tomohiro Matsuhashi and Yohei Ohno and Shugo Tohyama and Shinichiro Okata and Tomohisa Seki and Yusuke Kuroda and Kojiro Yae and Hisayuki Hashimoto and Tomofumi Tanaka and Fumiyuki Hattori and Toshiaki Sato and Shunichiro Miyoshi and Seiji Takatsuki and Mitsushige Murata and Junko Kurokawa and Tetsushi Furukawa and Naomasa Makita and Takeshi Aiba and Wataru Shimizu and Minoru Horie and Kaichiro Kamiya and Itsuo Kodama and Satoshi Ogawa and Keiichi Fukuda",

note = "Funding Information: This study was supported in part by research grants from the Ministry of Education, Science and Culture, Japan, by the Programme for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation and Health Labour Sciences Research Grant.",

year = "2012",

month = sep,

day = "1",

doi = "10.1093/cvr/cvs206",

language = "English",

volume = "95",

pages = "419--429",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - Disease characterization using LQTS-specific induced pluripotent stem cells

AU - Egashira, Toru

AU - Yuasa, Shinsuke

AU - Suzuki, Tomoyuki

AU - Aizawa, Yoshiyasu

AU - Yamakawa, Hiroyuki

AU - Matsuhashi, Tomohiro

AU - Ohno, Yohei

AU - Tohyama, Shugo

AU - Okata, Shinichiro

AU - Seki, Tomohisa

AU - Kuroda, Yusuke

AU - Yae, Kojiro

AU - Hashimoto, Hisayuki

AU - Tanaka, Tomofumi

AU - Hattori, Fumiyuki

AU - Sato, Toshiaki

AU - Miyoshi, Shunichiro

AU - Takatsuki, Seiji

AU - Murata, Mitsushige

AU - Kurokawa, Junko

AU - Furukawa, Tetsushi

AU - Makita, Naomasa

AU - Aiba, Takeshi

AU - Shimizu, Wataru

AU - Horie, Minoru

AU - Kamiya, Kaichiro

AU - Kodama, Itsuo

AU - Ogawa, Satoshi

AU - Fukuda, Keiichi

N1 - Funding Information: This study was supported in part by research grants from the Ministry of Education, Science and Culture, Japan, by the Programme for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation and Health Labour Sciences Research Grant.

PY - 2012/9/1

Y1 - 2012/9/1

N2 - Aims Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). Methods and resultsWe reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. ConclusionsThis study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

AB - Aims Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). Methods and resultsWe reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. ConclusionsThis study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

KW - Cardiomyocytes

KW - Drug examination

KW - Long QT syndrome

KW - Personalized medicine

KW - iPS cells

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U2 - 10.1093/cvr/cvs206

DO - 10.1093/cvr/cvs206

M3 - Article

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AN - SCOPUS:84865254838

SN - 0008-6363

VL - 95

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JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 4

ER -

Disease characterization using LQTS-specific induced pluripotent stem cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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