Immunomodulatory properties of umbilical cord blood-derived small extracellular vesicles and their therapeutic potential for inflammatory skin disorders

Abstract

Umbilical cord blood (UCB) has long been seen as a rich source of naive cells with strong regenerative potential, likely mediated by small extracellular vesicles (sEV). More recently, small extracellular vesicles (sEV), such as exosomes, have been shown to play essential roles in cell-to-cell communication, via the transport of numerous molecules, including small RNAs. Often explored for their potential as biomarkers, sEV are now known to have regenerative and immunomodulating characteristics, particularly if isolated from stem cell-rich tissues. In this study, we aim to characterize the immunomodulating properties of umbilical cord blood mononuclear cell sEV (herein referred as Exo-101), and explore their therapeutic potential for inflammatory skin diseases. Exo-101 was shown to shift macrophages toward an anti-inflammatory phenotype, which in turn exert paracrine effects on fibroblasts, despite previous inflammatory stimuli. Additionally, the incubation of PBMC with Exo-101 resulted in an reduction of total CD4+ and CD8+ T-cell proliferation and cytokine release, while specifically supporting the development of regulatory T-cells (Treg), by influencing FOXP3 expression. In a 3D model of psoriatic skin, Exo-101 reduced the expression of inflammatory and psoriatic markers IL-6, IL-8, CXCL10, COX-2, S100A7 and DEFB4. In vivo, Exo-101 significantly prevented or reversed acanthosis in imiquimod-induced psoriasis, and tendentially increased the number of Treg in skin, without having an overall impact on disease burden. This work provides evidence for the anti-inflammatory and tolerogenic effect of Exo-101, which may be harnessed for the treatment of Th17-driven inflammatory skin diseases, such as psoriasis.