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 journalArticle

98 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 languageEnglish
Pages (from-to)419-429
Number of pages11
JournalCardiovascular Research
Volume95
Issue number4
DOIs
Publication statusPublished - 2012 Sep 1

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Long QT Syndrome
Induced Pluripotent Stem Cells
Cardiac Myocytes
Embryoid Bodies
Precision Medicine
Mutation
Ion Channels
Cardiac Arrhythmias
Electrodes
Kidney

Keywords

  • Cardiomyocytes
  • Drug examination
  • iPS cells
  • Long QT syndrome
  • Personalized medicine

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

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

In: Cardiovascular Research, Vol. 95, No. 4, 01.09.2012, p. 419-429.

Research output: Contribution to journalArticle

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
Egashira, Toru ; Yuasa, Shinsuke ; Suzuki, Tomoyuki ; Aizawa, Yoshiyasu ; Yamakawa, Hiroyuki ; Matsuhashi, Tomohiro ; Ohno, Yohei ; Tohyama, Shugo ; Okata, Shinichiro ; Seki, Tomohisa ; Kuroda, Yusuke ; Yae, Kojiro ; Hashimoto, Hisayuki ; Tanaka, Tomofumi ; Hattori, Fumiyuki ; Sato, Toshiaki ; Miyoshi, Shunichiro ; Takatsuki, Seiji ; Murata, Mitsushige ; Kurokawa, Junko ; Furukawa, Tetsushi ; Makita, Naomasa ; Aiba, Takeshi ; Shimizu, Wataru ; Horie, Minoru ; Kamiya, Kaichiro ; Kodama, Itsuo ; Ogawa, Satoshi ; Fukuda, Keiichi. / Disease characterization using LQTS-specific induced pluripotent stem cells. In: Cardiovascular Research. 2012 ; Vol. 95, No. 4. pp. 419-429.
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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

PY - 2012/9/1

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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.

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KW - Cardiomyocytes

KW - Drug examination

KW - iPS cells

KW - Long QT syndrome

KW - Personalized medicine

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