Exosomes from adipose-derived stem cells accelerate wound healing by increasing the release of IL-33 from macrophages

Background: Mesenchymal stem cell (MSC) -derived exosomes, especially adipose-derived mesenchymal stem cell exosomes (ADSC-Exos), have emerged as a promising alternative for skin damage repair with anti-inflammatory, angiogenic and cell proliferation effects while overcoming some of the limitations of MSC. However, the mechanism by which ADSC-Exos regulates inflammatory cells during wound healing remains unclear. This study investigated how ADSC-Exos regulate macrophages to promote wound healing.

Methods: ADSC-Exos were isolated using ultracentrifugation, with subsequent quantification of exosomes particle number. To investigate their role in wound healing, the effects of ADSC-Exos on inflammation, angiogenesis, collagen deposition and macrophage polarization were evaluated through immunohistochemical staining, immunofluorescence and western blotting. Changes in gene expression associated with ADSC-Exos-induced macrophage polarization were analyzed using qPCR. RNA Sequencing was performed to identify differentially expressed genes affected by ADSC-Exos. The critical role of IL-33 in the wound healing process was further confirmed using Il33^-/- mice. Additionally, co-culture experiments were conducted to explore the effects of IL-33 on keratinocyte proliferation, collagen deposition and epithelialization.

Results: ADSC-Exos inhibited the expression of TNF-α and IL-6, induced M2 macrophage polarization, promoted collagen deposition and angiogenesis, and accelerated wound healing. RNA Sequencing identified IL-33 as a key mediator in this process. In Il33^-/- mice, impaired wound healing and decreased M2 macrophage polarization were observed. The co-culture experiments showed that IL-33 enhanced keratinocyte function through activation of the Wnt/β-catenin signaling pathway. These findings highlight the therapeutic potential of ADSC-Exos in wound healing by modulating IL-33.

Conclusions: ADSC-Exos promote wound healing by regulating macrophage polarization and enhancing IL-33 release which drives keratinocyte proliferation, collagen deposition and epithelialization via the Wnt/β-catenin signaling pathway. These findings provide a mechanistic basis for the therapeutic potential of ADSC-Exos in tissue repair and regeneration.

ADSC-Exos; IL-33; Inflammation; Macrophage; Wnt/β-catenin signaling pathway; Wound healing.