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Abstract
Hye Jin Hwang, MD,*† Woochul Chang, PHD,‡ Byeong-Wook Song, MS,†§ Heesang Song, PHD,∥ Min-Ji Cha, MS,†§ Il-Kwon Kim, PHD,†§ Soyeon Lim, PHD,¶ Eun Ju Choi, BS,†§ Onju Ham, BS,†§ Se-Yeon Lee, BS,†§ Jaemin Shim, MD,*† Boyoung Joung, MD, PHD,*† Hui-Nam Pak, MD, PHD,*† Sung Soon Kim, MD, PHD,*† Bum-Rak Choi, PHD,# Yangsoo Jang, MD, PHD,*†§** Moon-Hyoung Lee, MD, PHD,*† Ki-Chul Hwang, PHD†§**
Seoul, Incheon, and Gwangju Republic of Korea; and Providence, Rhode Island
From the *Cardiology Division, Yonsei University College of Medicine, Seoul, Republic of Korea; †Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; ‡Institute of Catholic Integrative Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Incheon, Republic of Korea; §Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; ∥Department of Biochemistry and Molecular Biology, Chosun University School of Medicine, Gwangju, Republic of Korea; ¶Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University Health System, Seoul, Republic of Korea; #Cardiovascular Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island; and the **Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. This research was supported by a Korea Science and Engineering Foundation (KOSEF) Grant funded by MOST (M1064102000106N410200110), grants from the Stem Cell Research Center of the 21st Century Frontier Research Program (SC-2150) and Basic Science Research Program through the National Research Foundation of Korea (7-2011-0267) funded by the Ministry of Education, Science, and Technology, and the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A085136). There was no industry involvement in the study. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Hwang, Chang, and Song contributed equally to this work.
Abstract
Objectives The purpose of this study was to evaluate the antiarrhythmic potential of mesenchymal stem cells (MSC) under a different environment.
Background Little is known about how environmental status affects antiarrhythmic potential of MSCs.
Methods To investigate the effect of paracrine factors secreted from MSCs under different circumstances on arrhythmogenicity in rats with myocardial infarction, we injected paracrine media (PM) secreted under hypoxic, normoxic conditions (hypoxic PM and normoxic PM), and MSC into the border zone of infarcted myocardium in rats.
Results We found that the injection of hypoxic PM, but not normoxic PM, markedly restored conduction velocities, suppressed focal activity, and prevented sudden arrhythmic deaths in rats. Underlying this electrophysiological alteration was a decrease in fibrosis, restoration of connexin 43, alleviation of Ca2+ overload, and recovery of Ca2+-regulatory ion channels and proteins, all of which is supported by proteomic data showing that several paracrine factors including basic fibroblast growth factor, insulinlike growth factor 1, hepatocyte growth factor, and EF-hand domain-containing 2 are potential mediators. When compared with PM, MSC injection did not reduce or prevent arrhythmogenicity, suggesting that the antiarrhythmic or proarrhythmic potential of MSC is mainly dependent on paracrine factors.
Conclusions A hypoxic or normoxic environment surrounding MSC affects the type and properties of the growth factors or cytokines, and these secreted molecules determine the characteristics of the electro-anatomical substrate of the surrounding myocardium.
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