Exosomes derived from M1 macrophages aggravate neointimal hyperplasia following carotid artery injuries in mice through miR-222/CDKN1B/CDKN1C pathway

Abstract

The role of M1 macrophages (M1M)-derived exosomes in the progression of neointimal hyperplasia remains unclear now. Using a transwell co-culture system, we demonstrated that M1M contributed to functional change of vascular smooth muscle cell (VSMC). We further stimulated VSMCs with exosomes isolated from M1M. Our results demonstrated that these exosomes could be taken up by VSMCs through macropinocytosis. Using a microRNA array assay, we identified that miR-222 originated from M1M-derived exosomes triggered the functional changes of VSMCs. In addition, we confirmed that miR-222 played a key role in promoting VSMCs proliferation and migration by targeting Cyclin Dependent Kinase Inhibitor 1B (CDKN1B) and Cyclin Dependent Kinase Inhibitor 1C (CDKN1C) in vitro. In vivo, M1M-derived exosomes significantly aggravated neointima formation following carotid artery ligation injury and wire injury and these effects were partly abolished by miR-222 inhibitor 2′OMe-miR-222. Our findings thus suggest that exosomes derived from M1M could aggravate neointimal hyperplasia through delivering miR-222 into VSMCs. Future studies are warranted to validate if the post-injury vascular neointimal hyperplasia and restenosis could be attenuated by inhibiting miR-222.

Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats

“…In addition, there is also evidence showing that exosomes derived from M1 macrophages may exert effects on neointimal hyperplasia via exosomal miRNAs. Exosomes derived from M1 macrophages were shown to aggravate neointimal hyperplasia by delivering miR-222 into VSMC [41]. Therefore, we hypothesized that MSC-Exo may be involved in the process of vascular endothelial cell regeneration and proliferation, which may further inhibit the progression of NIH after carotid injury in rats.…”

M2 macrophage-derived exosomes promote the c-KIT phenotype of vascular smooth muscle cells during vascular tissue repair after intravascular stent implantation

“…Exosomes from nicotine-treated macrophages accelerate the development of atherosclerosis by increasing VSMC migration and proliferation through its target PTEN 7 . Exosomes derived from M1 macrophages have been shown to aggravate neointimal hyperplasia by delivering miR-222 into VSMCs 8 . Nonetheless, there is still no definitive conclusion as to whether or how M2 macrophage exosomes affect the behavior of VSMCs during vascular tissue repair after stent implantation.…”

Extracellular vesicles therapy: opportunities, mechanisms and perspectives

“…Стволовые клетки немезенхимального происхождения выделяли из жировой ткани [8,35,37], использовали ство ловые клетки-предшественники нервной ткани [4,38], резидуальные стволовые клетки печени [16,20], а так же индуцированные плюрипотентные стволовые клетки (iPS cells) [48]. Иные клеточные источники: предшественники кардиомиоцитов [2,3,49], макрофаги [12,14,15,50,51], T-лимфоциты [44] и гранулоциты [43]. В ряде случаев ВВ получали не из клеточных культур, а из биологических жидкостей, например, семенной жидкости [52] и плазмы крови [14,52].…”

“…Снижение экспрессии гена SAA3, индуцированное везикулярной микроРНК-30b, способствовало уменьшению апоптоза и увеличению выживаемости альвеолоцитов [29]. МикроРНК-222 подавляла синтез циклин-зависимых киназ CDKN1B и CDKN1C в гладкомышечных клетках сосудов, что приводило к увеличению их пролиферации и миграции [51], а микроРНК-21, микроРНК-23a, микроРНК-125b, микроРНК-145 вызывали тот же эффект у фибробластов [36].…”

“…Эффекты от использования ВВ не всегда могут быть позитивными. Например, везикулярная микроРНК-222 увеличивала пролиферацию эндотелиоцитов (путём действия на ингибиторы CDK CDKN1B и CDKN1C), вследствие чего усиливалась гиперплазия интимы сонной артерии после её перевязки [51].…”