Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.
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.
['Liu|Haibo|H|', 'Gao|Wei|W|', 'Yuan|Jie|J|', 'Wu|Chaoneng|C|', 'Yao|Kang|K|', 'Zhang|Li|L|', 'Ma|Leilei|L|', 'Zhu|Jianbing|J|', 'Zou|Yunzeng|Y|', 'Ge|Junbo|J|']
D000818:Animals D001854:Bone Marrow Cells D015496:CD4-Positive T-Lymphocytes D015687:Cell Hypoxia D002465:Cell Movement D017077:Culture Media, Conditioned D016207:Cytokines D003713:Dendritic Cells D004195:Disease Models, Animal D055354:Exosomes D005786:Gene Expression Regulation D008213:Lymphocyte Activation D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009203:Myocardial Infarction D009206:Myocardium D032383:Myocytes, Cardiac D009336:Necrosis D061251:Primary Cell Culture D015398:Signal Transduction D013154:Spleen D014945:Wound Healing
Exosomes Dendritic cells Myocardial infarction Chemokines Cytokines T-lymphocytes