CCR7 Mediates Dendritic-Cell-Derived Exosome Migration and Improves Cardiac Function after Myocardial Infarction

Abstract

Dendritic cells (DCs) play key roles in promoting wound healing after myocardial infarction (MI). Our previous studies have shown that exosomes derived from DCs (DEXs) could migrate to lymphoid tissue and improve cardiac function post-MI by activating CD4+ T cells; however, the mechanism of DEXs’ migration to lymphoid tissue and the improvement of cardiac function are still unknown. In our study, we found that CCR7 expression significantly increased in MI-DEXs compared with control-DEXs; meanwhile, CCL19 and CCL21, the ligands of CCR7, significantly increased in the serum of MI-model mice. Subsequently, we overexpressed and knocked down CCR7 in MI-DEXs and found that overexpressed CCR7 enhanced the migration of MI-DEXs to the spleen; however, CCR7 knockdown attenuated MI-DEXs’ migration according to near-IR fluorescence imaging. Furthermore, overexpressed CCR7 in MI-DEXs enhanced the MI-DEXs’ improvement of cardiac function after MI; however, CCR7-knockdown MI-DEXs attenuated this improvement. In addition, after DEXs’ migration to the spleen, MI-DEXs activated CD4+ T cells and induced the expression of IL-4 and IL-10, which were significantly increased in the MI-DEX group compared with the control group. In conclusion, CCR7 could mediate DEXs’ migration to the spleen and improve cardiac function after MI, and we found that the mechanism was partly via activation of CD4+ T cells and secretion of IL-4 and IL-10. Our study presented an innovative method for improving cardiac function by enhancing the migration ability of MI-DEXs after MI, while CCR7 could be a potential candidate for MI-DEX bioengineering to enhance migration.

Membrane Vesicles as Drug Delivery Systems: Source, Preparation, Modification, Drug Loading, In Vivo Administration and Biodistribution, and Application in Various Diseases

“…Some studies have shown that extracellular vesicles exerted a better therapeutic efficacy than the cells releasing the EVs [ 6 ]. At present, abundant sources of membrane vesicles have been developed, including various biological fluids (e.g., blood, milk [ 7 , 8 ], orange juice [ 9 ]), animal cells (e.g., mesenchymal stem/stromal cells (MSCs) [ 7 , 10 , 11 ], dendritic cells [ 12 ], macrophages [ 13 ], tumor cells [ 14 ], red blood cells [ 15 ], different animal cell lines [ 16 ], and others), plant cells (e.g., grapes, conifers, ginger, garlic, tea, etc.) [ 17 ], bacteria (e.g., intestinal flora and probiotics) [ 18 , 19 , 20 ], and others [ 21 , 22 ].…”

“…The frequently used methods include differential ultrafiltration centrifugation (dUC), density gradient centrifugation, ultrafiltration (UF), precipitation, dimensional exclusion chromatography (SEC), and immunoaffinity capture, as well as emerging technologies (e.g., microfluidic) [ 6 ]. In this Special Issue, commercial ExoQuick-Tc TM Exosome Precipitation Solution was used for the isolation of dendritic cell-derived exosomes [ 12 ] and of human cell-secreted EVs [ 16 ]; differential ultracentrifugation method was used to separate EVs from mesenchymal/stromal stem cells [ 7 ] or from orange ( Citrus sinensis ) juice [ 9 ]; and density gradient centrifugation method was also utilized to prepare milk EVs [ 7 ].…”

“…At present, multiple methods have been applied for membrane vesicle modification, including modification of donor cells (e.g., genetic engineering modification), direct modification of isolated vesicles (e.g., chemical modification), combination strategy, and others [ 10 , 20 ]. In this Special Issue, modification of donor cells by regulating the expressions of CP05 [ 24 ], TRAIL [ 23 ], CD81 [ 16 ], CCR7 [ 12 ], etc., direct modifications of isolated EVs by using iRGD, hyaluronic acid, and folic acid [ 8 ], and combination modifications with αvβ3 integrin subunit and iRGD [ 23 ] were applied. Akbari et al reviewed the genetic and chemical functionalization of exosomes for tumor-targeted drug delivery [ 25 ].…”

“…A lot of related studies have been reported and summarized in many review articles. In this Special Issue, the applications of membrane vesicles as DDSs in bone-related diseases [ 14 ], anticancer and antimicrobial therapies [ 15 , 18 , 21 , 25 , 27 ], gastrointestinal diseases [ 17 , 19 ], organ transplant related diseases [ 31 ], cardiovascular diseases [ 10 , 12 , 32 ], neurodegenerative disorders [ 13 , 26 , 33 ], neurological anomalies associated with multidrug-resistant superbugs [ 20 ], and others were reviewed ( Figure 3 ). Since the application of probiotics in myocardial infarction has been reported [ 34 ], it seems also potential that the membrane vesicles derived from probiotics can be recruited as DDSs to treat cardiovascular diseases (e.g., myocardial infarction).…”

Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease

“…Transmission electron microscopy can reveal the double layer capsule structure of exosomes. Exosome surface markers, including CD63, CD81, CD9, TGS101, HSP70, and Alix, can be identified by using Western blot (WB). , …”