Exosomes from Adipose-derived Stem Cells Accelerate Wound Healing by Increasing the Release of IL-33 from Macrophages

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2025 Feb 21

PMID 39984984

Authors

Yichen Wang

Hongfan Ding

Ruiqi Bai

Qiang Li

Boyuan Ren

Pianpian Lin

Chengfei Li

Minliang Chen

Xiao Xu

Affiliations

Soon will be listed here.

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.

References

Ashcroft G, Jeong M, Ashworth J, Hardman M, Jin W, Moutsopoulos N . Tumor necrosis factor-alpha (TNF-α) is a therapeutic target for impaired cutaneous wound healing. Wound Repair Regen. 2011; 20(1):38-49. PMC: 3287056. DOI: 10.1111/j.1524-475X.2011.00748.x. View

Liu H, Zhang Y, Zhang Q, Wang Y, Ge R, Ma L . [Effects of human umbilical cord mesenchymal stem cells (MSCs)-derived exosomes on pulmonary vascular remodeling in hypoxic pulmonary hypertension]. Sheng Li Xue Bao. 2024; 76(1):33-44. View

Pitt J, Andre F, Amigorena S, Soria J, Eggermont A, Kroemer G . Dendritic cell-derived exosomes for cancer therapy. J Clin Invest. 2016; 126(4):1224-32. PMC: 4811123. DOI: 10.1172/JCI81137. View

Shen Z, Huang W, Liu J, Tian J, Wang S, Rui K . Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases. Front Immunol. 2021; 12:749192. PMC: 8503317. DOI: 10.3389/fimmu.2021.749192. View

Wang H, Wu T, Hua F, Sun J, Bai Y, Wang W . IL-33 Promotes ST2-Dependent Fibroblast Maturation via P38 and TGF-β in a Mouse Model of Epidural Fibrosis. Tissue Eng Regen Med. 2022; 19(3):577-588. PMC: 9130447. DOI: 10.1007/s13770-021-00425-1. View

Jin Z, Song Y, He L . A review of skin immune processes in acne. Front Immunol. 2024; 14:1324930. PMC: 10773853. DOI: 10.3389/fimmu.2023.1324930. View

Ni M, Wang Y, Yang J, Ma Q, Pan W, Li Y . IL-33 aggravates extranodal NK/T cell lymphoma aggressiveness and angiogenesis by activating the Wnt/β-catenin signaling pathway. Mol Cell Biochem. 2024; 480(1):265-278. DOI: 10.1007/s11010-024-04944-y. View

Tanaka T, Narazaki M, Masuda K, Kishimoto T . Regulation of IL-6 in Immunity and Diseases. Adv Exp Med Biol. 2016; 941:79-88. DOI: 10.1007/978-94-024-0921-5_4. View

Wang Y, Tatakis D . Integrative mRNA/miRNA expression analysis in healing human gingiva. J Periodontol. 2020; 92(6):863-874. DOI: 10.1002/JPER.20-0397. View

10.

Ding L, Ren J, Zhang D, Li Y, Huang X, Hu Q . A novel stromal lncRNA signature reprograms fibroblasts to promote the growth of oral squamous cell carcinoma via LncRNA-CAF/interleukin-33. Carcinogenesis. 2018; 39(3):397-406. DOI: 10.1093/carcin/bgy006. View

10.

Sui B, Chen J, Zhang X, He T, Zhao P, Zheng C . Gender-independent efficacy of mesenchymal stem cell therapy in sex hormone-deficient bone loss via immunosuppression and resident stem cell recovery. Exp Mol Med. 2018; 50(12):1-14. PMC: 6297134. DOI: 10.1038/s12276-018-0192-0. View

11.

Lee J, Seppanen E, Patel J, Rodero M, Khosrotehrani K . ST2 receptor invalidation maintains wound inflammation, delays healing and increases fibrosis. Exp Dermatol. 2015; 25(1):71-4. DOI: 10.1111/exd.12833. View

12.

Chan Y, Roy S, Khanna S, Sen C . Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2. Arterioscler Thromb Vasc Biol. 2012; 32(6):1372-82. PMC: 3399424. DOI: 10.1161/ATVBAHA.112.248583. View

13.

Naji A, Eitoku M, Favier B, Deschaseaux F, Rouas-Freiss N, Suganuma N . Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 2019; 76(17):3323-3348. PMC: 11105258. DOI: 10.1007/s00018-019-03125-1. View

14.

El Kasmi K, Stenmark K . Contribution of metabolic reprogramming to macrophage plasticity and function. Semin Immunol. 2015; 27(4):267-75. PMC: 4677817. DOI: 10.1016/j.smim.2015.09.001. View

15.

Pi L, Fang B, Meng X, Qian L . LncRNA XIST accelerates burn wound healing by promoting M2 macrophage polarization through targeting IL-33 via miR-19b. Cell Death Discov. 2022; 8(1):220. PMC: 9023461. DOI: 10.1038/s41420-022-00990-x. View

16.

DiLoreto R, Khush K, De Vlaminck I . Precision monitoring of immunotherapies in solid organ and hematopoietic stem cell transplantation. Adv Drug Deliv Rev. 2017; 114:272-284. DOI: 10.1016/j.addr.2017.06.009. View

17.

Oshio T, Komine M, Tsuda H, Tominaga S, Saito H, Nakae S . Nuclear expression of IL-33 in epidermal keratinocytes promotes wound healing in mice. J Dermatol Sci. 2016; 85(2):106-114. DOI: 10.1016/j.jdermsci.2016.10.008. View

18.

Zhang D, Lu Z, Man J, Cui K, Fu X, Yu L . Wnt-3a alleviates neuroinflammation after ischemic stroke by modulating the responses of microglia/macrophages and astrocytes. Int Immunopharmacol. 2019; 75:105760. DOI: 10.1016/j.intimp.2019.105760. View

19.

Fu X, Liu G, Halim A, Ju Y, Luo Q, Song A . Mesenchymal Stem Cell Migration and Tissue Repair. Cells. 2019; 8(8). PMC: 6721499. DOI: 10.3390/cells8080784. View