Exosome and Melatonin Additively Attenuates Inflammation by Transferring miR-34a, miR-124, and miR-135b

Abstract

The positive effects of mesenchymal stem cells (MSCs) are primarily activated through molecular secretions known as paracrine activity, which regulates the function of various cell types including immune cells. Accumulating evidence shows that exosomes of soluble factors released from MSCs are potential alternative agents for stem cell-based therapy, although the exact underlying mechanism has not been elucidated. The purpose of this study was to evaluate the potential effects of exosomes produced by adipose-derived MSCs and to examine the changes in anti-inflammatory genes in concurrence with the polarization of M2 macrophages in cellular models ex vivo. Isolated exosomes were used to investigate the inflammatory modulation in pro-inflammatory cytokine-treated fibroblasts and THP-1 cells. The anti-inflammatory mRNA expression associated with M2 macrophages was significantly upregulated after exosome treatment in an interferon gamma and tumor necrosis factor alpha-treated inflammatory environment. Furthermore, melatonin-stimulated exosomes exerted superior anti-inflammatory modulation via exosomal miRNAs miR-34a, miR-124, and miR-135b, compared with exosomes. Our results indicate that melatonin-stimulated exosomes originating from adipose-derived MSCs are safe and efficient tools for regenerative medicine to treat inflammatory diseases.

An Examination of the Putative Role of Melatonin in Exosome Biogenesis

“…Under other circumstances, such as lipopolysaccharide-induced Alzheimer's disease in rat neonates, melatonin decreases the pathological complications via the autophagy-SIRT-1 pathway and down-regulation of multiple miRNAs including miR-34a, -146a, and -126 (Meng et al, 2014;Carloni et al, 2016). Similarly, Heo et al (2020) showed that melatonin-stimulated exosomes isolated from adiposederived mesenchymal stem cells suppressed inflammation. These exosomes were enriched with multiple miRNAs such as miR-34a, -124, and -135b compared to non-treated melatonin exosomes.…”

The Application Potential and Advance of Mesenchymal Stem Cell-Derived Exosomes in Myocardial Infarction

“…Exosomes obtained from LPS preconditioning BMSCs can strongly increase M2 macrophage polarization and attenuated the postinfarction inflammation in a mouse MI model through inhibition of the LPSdependent NF-κB signaling pathway and activation of the AKT1/AKT2 signaling pathway [92]. Melatonin-stimulated exosomes derived from AD-MSCs can promote M2 macrophage differentiation and exerted superior anti-inflammatory modulation through miRNAs miR-34a, miR-124, and miR-135b [93]. Besides, several in vitro studies have also confirmed the immunosuppression and anti-inflammatory action of MSC-derived exosomes like miR-10a (facilitating Th17 and Treg responses) [94] and IDO (promoting the transformation of mononuclear cells to Tregs) [95].…”

Exosomes and Melatonin: Where Their Destinies Intersect

“…Also, in order to assess the potential effects of exosomes released by adipose tissue MSCs on inflammatory modulation, Heo et al (94) examined the changes in anti-inflammatory genes, along with the polarization of M2 macrophages in fibroblasts treated with pro-inflammatory cytokines and THP-1 cells. They observed that exosome treatment positively regulated the expression of anti-inflammatory mRNA associated with M2 macrophages, in an inflammatory environment treated with gamma interferon and tumor necrosis factor alpha.…”