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

  • Stem Cell Res Ther. 2025 Feb 21;16(1):80. doi: 10.1186/s13287-025-04203-x.
Yichen Wang  #  1  2 ,  Hongfan Ding  #  1 ,  Ruiqi Bai  1 ,  Qiang Li  3 ,  Boyuan Ren  3 ,  Pianpian Lin  1 ,  Chengfei Li  1 ,  Minliang Chen  4 ,  Xiao Xu  5
Affiliations
  • 1. Senior Department of Burns and Plastic Surgery, the Fourth Medical Center of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China.
  • 2. Chinese PLA Medical School , Beijing, 100853, China.
  • 3. Beijing Institute of Radiation Medicine, Beijing, 100850, China.
  • 4. Senior Department of Burns and Plastic Surgery, the Fourth Medical Center of Chinese PLA General Hospital, No. 51 Fucheng Road, Haidian District, Beijing, 100048, China. [email protected].
  • 5. Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, No. 69 Yongding Road, Haidian District, Beijing, 100039, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 39984984 DOI: 10.1186/s13287-025-04203-x
Abstract

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.

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