Infarcted Myocardium-Primed Dendritic Cells Improve Remodeling and Cardiac Function After Myocardial Infarction by Modulating the Regulatory T Cell and Macrophage Polarization.
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.
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.).
Eun Ho
EH
Choo
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.).
Jun-Ho
JH
Lee
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.).
Eun-Hye
EH
Park
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.).
Hyo Eun
HE
Park
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.).
Nam-Chul
NC
Jung
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.).
Tae-Hoon
TH
Kim
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.).
Yoon-Seok
YS
Koh
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.).
Eunmin
E
Kim
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.).
Ki-Bae
KB
Seung
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.).
Cheongsoo
C
Park
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.).
Kwan-Soo
KS
Hong
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.).
Kwonyoon
K
Kang
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.).
Jie-Young
JY
Song
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.).
Han Geuk
HG
Seo
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.).
Dae-Seog
DS
Lim
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.
Kiyuk
K
Chang
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D015415:Biomarkers; D002465:Cell Movement; D064987:Cell- and Tissue-Based Therapy; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D007114:Immunization; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000175:diagnosis* / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D000941:Antigens; D015415:Biomarkers
dendritic cells; heart failure; macrophage; myocardial infarction; regulatory T-cells; ventricular remodeling