Exosomes of Adipose Tissue–Derived Stem Cells Promote Wound Healing by Sponging miR-17-5p and Inducing Autophagy Protein Ulk1

Abstract

Background: Wound healing undergoes intricate phases: hemostasis, inflammation, proliferation, and remodeling. Stem cell therapy based on adipose tissue–derived stem cell exosomes (ADSCs-exo) is considered a potential effective treatment for accelerating wound healing. However, the molecular mechanisms of wound healing using ADSCs-exo remain largely unknown. Methods: Circular wounds, 1 × 1 cm, were generated on C57BL/6 mice, followed by OriCell C57BL/6 mouse adipose-derived mesenchymal stem cell suspension treatment, and wound area was measured and recorded at days 0, 7, and 21, respectively. A comprehensive transcriptome profiling of skin wounds was conducted in the mouse model. Importantly, the authors also examined autophagy and cell migration in mouse keratinocytes treated with ADSCs-exo. Further competing endogenous RNA networks were also used to reveal the relationship between Neat1 and Ulk1. Results: Mouse keratinocytes treated with ADSCs-exo showed significant up-regulation of pathways related to wound healing, including response to virus, bacterium, immune system, and wounding. Activated autophagy was detected, which significantly promoted the wound repair of mice. Competing endogenous RNA networks uncovered that Neat1 induces the expression of Ulk1 and thus up-regulates autophagic activity to promote wound repair through sponging miR-17-5p. Conclusions: Collectively, these results reveal a novel molecular mechanism that the autophagy pathway enhanced by the Neat1/miR-17-5p/Ulk1 axis can promote the wound healing and suggest that long noncoding RNA Neat1 loaded by ADSCs-exo might be a potential therapeutic target for skin nonhealing wounds. Clinical Relevance Statement: This study may provide new clues for the applications of ADSCs-exo in skin wounds and promote the development of ADSCs-exo therapy in clinical treatment of skin wounds.