Exosome-Like Vesicles from <i>Lithospermum erythrorhizon</i> Callus Enhanced Wound Healing by Reducing LPS-Induced Inflammation

Abstract

IntroductionThe skin, the largest organ in mammals, plays an indispensable role in maintaining homeostasis, offering protection against environmental assaults such as pathogens, ultraviolet (UV) radiation, and physical trauma.Its primary function as a barrier is crucial for preventing excessive water loss and microbial invasion, thus preserving the body's internal environment.When the skin is injured due to trauma, burns, or surgery, it initiates a complex and dynamic wound healing process that progresses through four overlapping stages: hemostasis, inflammation, proliferation, and tissue remodeling [1][2][3].The efficient orchestration of these stages is vital to restoring the skin's structural and functional integrity.Inflammation, the second phase of wound healing, is pivotal in clearing pathogens and cellular debris from the wound site.This inflammatory phase is marked by the recruitment of immune cells such as neutrophils, macrophages, and lymphocytes, which help to initiate the subsequent tissue repair processes [4, 5] However, when inflammation is excessive or dysregulated, it can lead to delayed wound healing, tissue damage, or chronic wounds, particularly in conditions associated with bacterial infections, immune dysfunctions, or metabolic diseases like diabetes [6].Lipopolysaccharide (LPS), a component of Gram-negative bacterial membranes, is often used in experimental models to simulate inflammation-related delays in wound healing by inducing a robust immune response [7][8][9].Recent advances in regenerative medicine have highlighted the significance of extracellular vesicles (EVs) as mediators of intercellular communication, particularly in modulating inflammation and promoting tissue regeneration [10,11].EVs are lipid bilayer-enclosed particles that carry proteins, lipids, and nucleic acids, and capable of transferring bioactive molecules between cells, influencing various biological processes including immune modulation and tissue repair [12].Among EVs, exosome-like vesicles have garnered attention for their Lithospermum erythrorhizon (LE), a medicinal plant from the Boraginaceae family, is traditionally used in East Asia for its therapeutic effects on skin conditions, including infections, inflammation, and wounds.Recently, the role of extracellular vesicles (EVs) as mediators of intercellular communication that regulate inflammation and promote tissue regeneration has garnered increasing attention in the field of regenerative medicine.This study investigates exosome-like vesicles derived from LE callus (LELVs) and their potential in enhancing wound healing.In vitro studies using normal human dermal fibroblasts (NHDFs) demonstrated that LELVs significantly improved cell viability, proliferation, and wound closure, while also enhancing collagen type I synthesis, indicating anti-inflammatory and regenerative properties.For in vivo analysis, LELVs were applied to lipopolysaccharide (LPS)induced wounds in mice, where wound healing progression was monitored over 14 days.LELVtreated wounds exhibited accelerated re-epithelialization, reduced inflammation, and improved tissue remodeling, with histological analysis revealing enhanced collagen deposition and reduced inflammatory cell infiltration.These results highlight the ability of LELVs to modulate the inflammatory response and promote wound healing.With their natural origin, low immunogenicity, and ease of production, LELVs represent a promising alternative to synthetic treatments for inflammation-associated skin injuries and hold significant potential for clinical applications in wound care.

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