title: Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.
abstract: CD4(+) T cell activation plays a key role in facilitating wound healing after myocardial infarction (MI). Exosomes (EXs) secreted from dendritic cells (DCs) can activate T cells in tumor models; however, whether DEXs (DC-EXs) can mediate CD4(+) T cell activation and improve wound healing post-MI remains unknown. This study sought to determine whether DEXs mediate CD4(+) T cell activation and improve cardiac function post-MI in mice. We used supernatants of hypoxic primary or necrotic HL-1 cardiomyocytes to simulate the post-MI cardiomyocyte microenvironment in vitro. Cultured bone marrow-derived DCs (BMDCs) from mice were stimulated with the supernatants of normal (Control group), hypoxic primary or necrotic HL-1 cardiomyocytes (MI group); a subset of BMDCs remained unstimulated (Negative group). DEXs were then isolated from the BMDC supernatants and either incubated with CD4(+) T cells or injected into mice via the tail vein. In this study, we found that the supernatants of both hypoxic primary and necrotic HL-1 cardiomyocytes upregulate DC maturation markers. After the injection of DEXs, a greater number of MI-DEXs are recruited by the mouse spleen and with greater rapidity than control- or negative-DEXs. Confocal imaging and flow cytometry revealed that MI-DEXs exhibited higher uptake by splenic CD4(+) T cells than the control- and negative-DEXs, and this increase was correlated with significantly greater increases in the expression of chemokines and the inflammatory cytokines IFN-γ and TNF by the CD4(+) T cells in vitro and in vivo. In addition, the injection of MI-DEXs improved cardiac function in mice post-MI. These results suggest that DEXs could mediate the activation of CD4(+) T cells through an endocrine mechanism and improve cardiac function post-MI. Our findings provide the basis for a novel strategy for the treatment of MI through the systemic delivery of DEXs.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China; Department of Cardiology, Yinzhou People's Hospital Affiliated with the Medical School of Ningbo University, 315040 Ningbo; PR China. Electronic address: haiboliu13@fudan.edu.cn.
authors.forename: Haibo
authors.initials: H
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: govee@aliyun.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: yuanjieww@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: wuchao1107@126.com.
authors.forename: Chaoneng
authors.initials: C
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: yao.kang@zs-hospital.sh.cn.
authors.forename: Kang
authors.initials: K
authors.lastname: Yao
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: eileen910128@gmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: mllsdjn@126.com.
authors.forename: Leilei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: zhujianbing543@163.com.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: zou.yunzeng@zs-hospital.sh.cn.
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, PR China. Electronic address: jbge@zs-hospital.sh.cn.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015687:Cell Hypoxia; D002465:Cell Movement; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D055354:Exosomes / Q000276:immunology / Q000637:transplantation*; D005786:Gene Expression Regulation; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000534:rehabilitation / Q000628:therapy*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009336:Necrosis / Q000276:immunology / Q000473:pathology / Q000534:rehabilitation / Q000628:therapy*; D061251:Primary Cell Culture; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014945:Wound Healing / Q000187:drug effects / Q000276:immunology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines
keywords: Chemokines; Cytokines; Dendritic cells; Exosomes; Myocardial infarction; T-lymphocytes