Mesenchymal stem cell-derived exosomal miR-21a-5p promotes M2 macrophage polarization and reduces macrophage infiltration to attenuate atherosclerosis

摘要

Atherosclerosis(AS)is the main pathological basis for ischemic cardiovascular and cerebrovascu-lar diseases.Mesenchymal stem cell(MSC)-derived exosomes have the potential to alleviate AS,while the underlying mechanism remains unclear.Hlere,we aimed to investigate the mechanism of MSC-derived exosomes in AS.The AS mouse model was prepared by feeding ApoE-/-mice with high-fat diet.AS mice were administered with MSC-derived exosomes,and the atherosclerotic plaque area was analyzed by Oil Red O staining.Mouse RAW264.7 macrophages were incu-bated with MSC-derived exosomes.The macrophage infiltration,macrophage proportion,and cell migration were estimated by immunohistochemistry,flow cytometry,or Transwell assay.The relationship between miR-21a-5p and kruppel-like factor 6(KLF6)or extracellular signal-regulated protein kinases 2(ERK2)was verified by luciferase reporter assay.We found that MSC-derived exosomes promoted M2 polarization of macrophages and reduced plaque area and macrophage infiltration in AS mice.miR-21a-5p overexpression caused an increase of M2 macrophages in RAW264.7 cells and led to a decrease in migration of RAW264.7 cells.Moreover,both KLF6 and ERK2 are the targets of miR-21a-5p.MSC-derived exosomes containing miR-21a-5p promoted M2 polarization of RAW264.7 cells by suppressing KLF6 expression.MSC-derived exosomes contain-ing miR-21a-5p inhibited migration of RAW264.7 cells through inhibiting the ERK1/2 signaling path-way.In conclusion,MSC-derived exosomes containing miR-21a-5p promote macrophage polariza-tion and reduce macrophage infiltration by targeting KLF6 and ERK1/2 signaling pathways,thereby attenuating the development of AS.Thus,MSC-derived exosomes may be a promising treatment for AS.