Disease characterization using LQTS-specific induced pluripotent stem cells

作者：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

来源：Cardiovascular Research, 2012, 95(4): 419-429.

DOI：10.1093/cvr/cvs206

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

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). %26lt;br%26gt;We 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. %26lt;br%26gt;This 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.

• 出版日期2012-9-1