Plasma-Derived Exosomes Boost the Healing of Irradiated Wound by Regulating Cell Proliferation and Ferroptosis

Abstract

Ionizing radiation (IR) therapy for malignant tumors can damage adjacent tissues, leading to severe wound complications. Plasma-derived exosome treatment has recently emerged as a safe and impactful cell-free therapy. Herein, we aimed to determine whether plasma-derived exosomes could improve the healing of post-radiation wound. Rat plasma-derived exosomes (RP-Exos) were locally injected on cutaneous wounds created on the backs of irradiated rats and boosted the healing process as well as the deposition and remodeling of the extracellular matrix with collagen formation. Subsequently, the effects of RP-Exos were further evaluated on irradiated fibroblasts in vitro. The results suggested that exosomes promoted fibroblast proliferation, migration, cell cycle progression, and cell survival. Moreover, transcriptome sequencing analysis and quantitative polymerase chain reaction validation were performed to identify potential mechanisms. RPExos enhanced the expression of cell proliferation and radioresistance-related genes, and yet downregulated ferroptosis pathway in irradiated fibroblasts. Inhibition of ferroptosis by RP-Exos was further confirmed through colorimetric assay, fluorescence probe and flow cytometry in ferroptosis-induced fibroblasts. Our results suggest that RP-Exos regulate cell proliferation and ferroptosis in irradiated fibroblasts, thereby boosting the healing of irradiated wound. These findings support plasma-derived exosomes as a potential therapeutic method for post-radiation wound complications.

Micro-RNA and Proteomic Profiles of Plasma-Derived Exosomes from Irradiated Mice Reveal Molecular Changes Preventing Apoptosis in Neonatal Cerebellum

“…Similarly, a lower level of apoptosis was observed in irradiated endothelial cells when pre-incubated with EVs from irradiated donors, suggesting an anti-apoptotic function [77]. In accordance with our findings, rat plasma-derived exosomes have also been shown to promote proliferation, migration, and cellular survival in irradiated fibroblasts, improving the healing of cutaneous post-radiation wound when locally injected [78].…”

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

“…It promotes the formation of ferritin-containing multivesicular bodies (MVBs) and exosomes that transport iron out of the cell and thus inhibits ferroptosis ( Brown et al, 2019 ). Exosomes themselves are also proved to have some curing functions; for instance, rat plasma-derived exosomes can enhance cell proliferation and radio-resistance-related genes and yet downregulate ferroptosis in irradiated fibroblasts ( Gan et al, 2021 ).…”

Physiological Effects of Ferroptosis on Organ Fibrosis

“…Local injection of rat plasma-derived exosomes (RP-Exos) into the cutaneous wounds on the backs of irradiated rats promotes ECM remodeling and collagen production. In vitro studies indicated that RP-Exos increased the expression of genes related to cell proliferation and radioresistance but downregulated the ferroptotic death pathway in irradiated fibroblasts, thereby promoting the coalescence of irradiated wounds [ 121 ]. Approaches that promote tissue repair and healing by inhibiting ferroptosis suggest that the internal connection between ferroptosis and fibrosis has broadened the diagnosis and treatment of certain diseases.…”