Eun Ho Choo1, Jun-Ho Lee1, Eun-Hye Park1, Hyo Eun Park1, Nam-Chul Jung1, Tae-Hoon Kim1, Yoon-Seok Koh1, Eunmin Kim1, Ki-Bae Seung1, Cheongsoo Park1, Kwan-Soo Hong1, Kwonyoon Kang1, Jie-Young Song1, Han Geuk Seo1, Dae-Seog Lim1, Kiyuk Chang2. 1. From Cardiology Division, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea (E.H.C., E.-H.P., H.E.P., T.-H.K., Y.-S.K., E.K., K.-B.S., K.K., K.C.); Department of Biotechnology, CHA University, Seongnam-si, Gyeonggi-do, Korea (J.-H.L., D.-S.L.); Pharos Vaccine Inc, Seongnam-si, Gyeonggido, Korea (J.-H.L., N.-C.J.); Division of Magnetic Resonance Research, Korea Basic Science Institute, Cheongju-si, Chungcheongbuk- do, Korea (C.P., K.-S.H.); Department of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul (J.-Y.S.); and Department of Animal Biotechnology, Konkuk University, Seoul, Korea (H.G.S.). 2. From Cardiology Division, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea (E.H.C., E.-H.P., H.E.P., T.-H.K., Y.-S.K., E.K., K.-B.S., K.K., K.C.); Department of Biotechnology, CHA University, Seongnam-si, Gyeonggi-do, Korea (J.-H.L., D.-S.L.); Pharos Vaccine Inc, Seongnam-si, Gyeonggido, Korea (J.-H.L., N.-C.J.); Division of Magnetic Resonance Research, Korea Basic Science Institute, Cheongju-si, Chungcheongbuk- do, Korea (C.P., K.-S.H.); Department of Radiation Cancer Sciences, Korea Institute of Radiological and Medical Sciences, Seoul (J.-Y.S.); and Department of Animal Biotechnology, Konkuk University, Seoul, Korea (H.G.S.). kiyuk@catholic.ac.kr dslim@cha.ac.kr.
Abstract
BACKGROUND: Inflammatory responses play a critical role in left ventricular remodeling after myocardial infarction (MI). Tolerogenic dendritic cells (tDCs) can modulate immune responses, inducing regulatory T cells in a number of inflammatory diseases. METHODS: We generated tDCs by treating bone marrow-derived dendritic cells with tumor necrosis factor-α and cardiac lysate from MI mice. We injected MI mice, induced by a ligation of the left anterior descending coronary artery in C57BL/6 mice, twice with tDCs within 24 hours and at 7 days after the ligation. RESULTS: In vivo cardiac magnetic resonance imaging and ex vivo histology confirmed the beneficial effect on postinfarct left ventricular remodeling in MI mice treated with tDCs. Subcutaneously administered infarct lysate-primed tDCs near the inguinal lymph node migrated to the regional lymph node and induced infarct tissue-specific regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, indicating that a local injection of tDCs induces a systemic activation of MI-specific regulatory T cells. These events elicited an inflammatory-to-reparative macrophage shift. The altered immune environment in the infarcted heart resulted in a better wound remodeling, preserved left ventricular systolic function after myocardial tissue damage, and improved survival. CONCLUSIONS: This study showed that tDC therapy in a preclinical model of MI was potentially translatable into an antiremodeling therapy for ischemic tissue repair.
BACKGROUND: Inflammatory responses play a critical role in left ventricular remodeling after myocardial infarction (MI). Tolerogenic dendritic cells (tDCs) can modulate immune responses, inducing regulatory T cells in a number of inflammatory diseases. METHODS: We generated tDCs by treating bone marrow-derived dendritic cells with tumor necrosis factor-α and cardiac lysate from MI mice. We injected MI mice, induced by a ligation of the left anterior descending coronary artery in C57BL/6 mice, twice with tDCs within 24 hours and at 7 days after the ligation. RESULTS: In vivo cardiac magnetic resonance imaging and ex vivo histology confirmed the beneficial effect on postinfarct left ventricular remodeling in MI mice treated with tDCs. Subcutaneously administered infarct lysate-primed tDCs near the inguinal lymph node migrated to the regional lymph node and induced infarct tissue-specific regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, indicating that a local injection of tDCs induces a systemic activation of MI-specific regulatory T cells. These events elicited an inflammatory-to-reparative macrophage shift. The altered immune environment in the infarcted heart resulted in a better wound remodeling, preserved left ventricular systolic function after myocardial tissue damage, and improved survival. CONCLUSIONS: This study showed that tDC therapy in a preclinical model of MI was potentially translatable into an antiremodeling therapy for ischemic tissue repair.
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Authors: Mohammad Javad Hajipour; Mehdi Mehrani; Seyed Hesameddin Abbasi; Ahmad Amin; Seyed Ebrahim Kassaian; Jessica C Garbern; Giulio Caracciolo; Steven Zanganeh; Mitra Chitsazan; Haniyeh Aghaverdi; Seyed Mehdi Kamali Shahri; Aliakbar Ashkarran; Mohammad Raoufi; Holly Bauser-Heaton; Jianyi Zhang; Jochen D Muehlschlegel; Anna Moore; Richard T Lee; Joseph C Wu; Vahid Serpooshan; Morteza Mahmoudi Journal: Chem Rev Date: 2019-09-06 Impact factor: 60.622