Fibroblast exosomes promote wound healing and improve the quality of healed skin via miR-29a-3p-mediated KEAP1/Nrf2 pathway activation

Abstract

Background: Wound healing is a sophisticated biological process characterized by the orchestrated interplay of diverse cellular components, growth factors, and signaling cascades. Recent research has highlighted the pivotal role of fibroblast exosomes in mediating intercellular communication and facilitating tissue regeneration. This investigation aimed to elucidate the therapeutic efficacy of fibroblast exosomes in enhancing wound repair mechanisms, with a particular emphasis on their differential effects in normal and diabetic wound healing paradigms. Methods: A mouse full-thickness skin defect model was used to evaluate the effects of fibroblast exosomes on wound re-epithelialization, granulation tissue formation, and epidermal barrier function. Molecular and cellular experiments were conducted to analyze the roles of exosomes in epidermal stem cell proliferation, migration, differentiation, and antioxidant stress, with further validation of the associated signaling pathways. The therapeutic efficacy was additionally confirmed in a type 1 diabetic mouse model. Results: Fibroblast exosomes significantly enhanced wound re-epithelialization by promoting the proliferation, migration, and differentiation of epidermal stem cells. Additionally, exosomes increased fibroblast abundance and myofibroblast activation, facilitating granulation tissue formation as well as improving extracellular matrix (ECM) deposition and the biomechanical properties of healed skin. Furthermore, exosomes improved epidermal barrier function by upregulating tight junction proteins (e.g. Claudin-1 and ZO-1) and reducing transepidermal water loss (TEWL). In diabetic mouse models, exosomes accelerated wound closure, restored ECM deposition and biomechanical integrity, and repaired epidermal barrier function. Mechanistically, exosomes target the 3′ untranslated region (UTR) of Keap1 mRNA through miR-29a-3p and activate the KEAP1/Nrf2 antioxidant pathway, mitigating oxidative stress and protecting epidermal stem cells from reactive oxygen species (ROS)-induced damage. Conclusion: Fibroblast exosomes alleviate oxidative damage by modulating the KEAP1/Nrf2 pathway through miR-29a-3p and enhancing epidermal stem cell function. These exosomes exhibit remarkable therapeutic potential in accelerating wound healing and improving healing quality under both normal and diabetic conditions, offering a robust foundation for innovative therapeutic strategies.

Keywords

Fibroblast exosomes / Wound healing / Biomechanical integrity / Epidermal barrier / KEAP1/Nrf2 pathway

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