Exosomal miR-27a-3p derived from tumor-associated macrophage suppresses propranolol sensitivity in infantile hemangioma

Abstract Propranolol is the first-line drug for infantile hemangioma (IH) therapy, whereas propranolol resistance is clinically observed. Tumor-associated macrophages (TAMs)-derived exosomes may deliver biological molecules to promote tumor progression. Here, we aimed to investigate the relationship between TAMs-derived exosomal miR-27a-3p and propranolol sensitivity in IH. Human peripheral blood monocytes (PBMCs) were cultured with macrophage colony-stimulating factor (M-CSF) for 7 days to get unactivated macrophages (Un-Mac), which were further treated with IL-4 and IL-13 to induce M2 polarized macrophages. Exosomes were isolated from the conditioned medium of M2 macrophage, followed by identification. Cell co-culture and/or transfection were performed to explore whether M2 polarized macrophage-derived exosomes (M2-exos) could mediate the crosstalk between TAMs-derived miR-27a-3p and hemangioma stem cells (HemSCs). In addition, nude mice were subcutaneously transplanted with HemSCs pretreated with or without M2-Exos to examine the effects of M2-Exos on IH in vivo. M2 polarized macrophages inhibited propranolol sensitivity of HemSCs, as shown by the increased cell viability and decreased apoptosis. miR-27a-3p was upregulated in M2 polarized macrophages and M2-Exos. Moreover, M2-exos delivered miR-27a-3p from macrophages to HemSCs and subsequently reduced propranolol sensitivity. Luciferase reporter and biotin-RNA pulldown assay proved that dickkopf-related protein 2 (DKK2) was the direct target of miR-27a-3p. These results demonstrate that M2-exos could deliver miR-27a-3p from macrophages to HemSCs to reduce the sensitivity of HemSCs to propranolol by down-regulating DKK2 expression, and exosomal miR-27a-3p and DKK2 in HemSCs could be considered as treatment targets.