Exosomes Derived from Minor Salivary Gland Mesenchymal Stem Cells: a Promising Novel Exosome Exhibiting Pro-angiogenic and Wound Healing Effects Similar to Those of Adipose-derived Stem Cell Exosomes

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2024 Dec 4

PMID 39627883

Authors

Haibo Xiang

Pengbing Ding

Jiaying Qian

Enhang Lu

Yimou Sun

Seyeon Lee

Zhenkun Zhao

Zhixuan Sun

Zhenmin Zhao

Affiliations

Soon will be listed here.

Abstract

Backgrounds: Minor salivary gland mesenchymal stem cells (MSGMSCs) can be easily extracted and have a broad range of sources. Applying exosomes to wounds is a highly promising method for promoting wound healing. Exosomes derived from different stem cell types have been proven to enhance wound healing, with adipose-derived stem cell (ADSC)-derived exosomes being the most extensively researched. Considering that MSGMSCs have advantages such as easier extraction compared to ADSCs, MSGMSCs should also be a very promising type of stem cell in exosome therapy. However, whether MSGMSC-derived exosomes (MSGMSC-exos) can promote wound healing and how they compare to ADSC-derived exosomes (ADSC-exos) in the wound healing process remain unclear.

Materials: The effects of MSGMSC-exos and ADSC-exos on angiogenesis in wound healing were investigated in vitro using CCK-8, scratch assays, and tube formation assays. Subsequently, the promotion of wound healing by MSGMSC-exos and ADSC-exos was evaluated in vivo using a full-thickness wound defect model in mice. Immunohistochemistry was used to verify the effects of MSGMSC-exos and ADSC-exos on promoting collagen deposition, angiogenesis, and cell proliferation in the wound. Immunofluorescence staining was performed to investigate the role of MSGMSC-exos and ADSC-exos in modulating the inflammatory response in the wound. Furthermore, proteomic sequencing was conducted to investigate the functional similarities and differences between the proteomes of MSGMSC-exos and ADSC-exos, with key protein contents verified by ELISA.

Results: MSGMSC-exos exhibited similar effects as ADSC-exos in promoting the migration, proliferation, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, with a comparable dose-dependent effect. In vivo experiments confirmed that MSGMSC-exos have similar wound healing-promoting functions as ADSC-exos. MSGMSC-exos promoted the neovascularization and maturation of blood vessels in vivo at a level comparable to ADSC-exos. Despite MSGMSC-exos showing less collagen deposition than ADSC-exos, they exhibited stronger anti-scar formation and anti-inflammatory effects. Proteomic analysis revealed that the proteins promoting wound healing in both MSGMSC-exos and ADSC-exos were relatively conserved, with ITGB1 identified as a critical protein for angiogenesis. Further differential analysis revealed that the functions specifically enriched in MSGMSC-exos and ADSC-exos reflected the functions of their source tissue.

Conclusions: Our study confirms that MSGMSC-exos exhibit highly similar wound healing and angiogenesis-promoting functions compared to ADSC-exos, and the proteins involved in promoting wound healing in both are relatively conserved. Moreover, MSGMSC-exos show stronger anti-scar formation and anti-inflammatory effects than ADSC-exos. This suggests that MSGMSCs are a promising stem cell source with broad applications in wound healing treatment.

References

Zhou Y, Zhang X, Lu S, Zhang N, Zhang H, Zhang J . Human adipose-derived mesenchymal stem cells-derived exosomes encapsulated in pluronic F127 hydrogel promote wound healing and regeneration. Stem Cell Res Ther. 2022; 13(1):407. PMC: 9358082. DOI: 10.1186/s13287-022-02980-3. View

Kessler A, Bhatt A . Review of the Major and Minor Salivary Glands, Part 1: Anatomy, Infectious, and Inflammatory Processes. J Clin Imaging Sci. 2018; 8:47. PMC: 6251248. DOI: 10.4103/jcis.JCIS_45_18. View

Liang X, Zhang L, Wang S, Han Q, Zhao R . Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci. 2016; 129(11):2182-9. DOI: 10.1242/jcs.170373. View

Phimnuan P, Dirand Z, Tissot M, Worasakwutiphong S, Sittichokechaiwut A, Grandmottet F . Beneficial Effects of a Blended Fibroin/Aloe Gel Extract Film on the Biomolecular Mechanism(s) the MAPK/ERK Pathway Relating to Diabetic Wound Healing. ACS Omega. 2023; 8(7):6813-6824. PMC: 9948169. DOI: 10.1021/acsomega.2c07507. View

Boyce D, Shokrollahi K . Reconstructive surgery. BMJ. 2006; 332(7543):710-2. PMC: 1410906. DOI: 10.1136/bmj.332.7543.710. View

Bellavia S, Gallara R . Effect of photic stimuli on rat salivary glands. Role of sympathetic nervous system. Acta Odontol Latinoam. 2002; 13(1):3-19. View

Lorenz L, Axnick J, Buschmann T, Henning C, Urner S, Fang S . Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival. Nature. 2018; 562(7725):128-132. DOI: 10.1038/s41586-018-0522-3. View

Yang X, Wang S, Yu W, Zheng Y, Wu Y . Inhibition of ITGB1 enhance the anti-tumor effect of cetuximab in colorectal cancer cell. Medicine (Baltimore). 2020; 99(27):e20944. PMC: 7337548. DOI: 10.1097/MD.0000000000020944. View

Xu X, Yin F, Guo M, Gan G, Lin G, Wen C . Quantitative proteomic analysis of exosomes from umbilical cord mesenchymal stem cells and rat bone marrow stem cells. Proteomics. 2022; 23(1):e2200204. DOI: 10.1002/pmic.202200204. View

10.

Schnoell J, Jank B, Kadletz-Wanke L, Stoiber S, Gurnhofer E, Schlederer M . Protein Expression of Folate Receptor Alpha in Adenoid Cystic Carcinoma of the Head and Neck. Onco Targets Ther. 2022; 15:531-538. PMC: 9122665. DOI: 10.2147/OTT.S351500. View

11.

Whitaker R, Hernaez-Estrada B, Hernandez R, Santos-Vizcaino E, Spiller K . Immunomodulatory Biomaterials for Tissue Repair. Chem Rev. 2021; 121(18):11305-11335. DOI: 10.1021/acs.chemrev.0c00895. View

12.

Peled Z, Phelps E, Updike D, Chang J, Krummel T, Howard E . Matrix metalloproteinases and the ontogeny of scarless repair: the other side of the wound healing balance. Plast Reconstr Surg. 2002; 110(3):801-11. DOI: 10.1097/00006534-200209010-00013. View

13.

Zheng Q, Gong Z, Li B, Cheng R, Luo W, Huang C . Identification and characterization of CLEC11A and its derived immune signature in gastric cancer. Front Immunol. 2024; 15:1324959. PMC: 10859539. DOI: 10.3389/fimmu.2024.1324959. View

14.

Zhang X, Ding P, Chen Y, Lin Z, Zhao X, Xie H . Human umbilical cord mesenchymal stem cell-derived exosomes combined with gelatin methacryloyl hydrogel to promote fractional laser injury wound healing. Int Wound J. 2023; 20(10):4040-4049. PMC: 10681517. DOI: 10.1111/iwj.14295. View

15.

Nie F, Ding P, Zhang C, Zhao Z, Bi H . Extracellular vesicles derived from lipoaspirate fluid promote fat graft survival. Adipocyte. 2021; 10(1):293-309. PMC: 8172157. DOI: 10.1080/21623945.2021.1932355. View

16.

Zhang T, Wang X, Wang Z, Lou D, Fang Q, Hu Y . Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation. Biomed Pharmacother. 2020; 129:110287. DOI: 10.1016/j.biopha.2020.110287. View

17.

DiPietro L . Angiogenesis and wound repair: when enough is enough. J Leukoc Biol. 2016; 100(5):979-984. PMC: 6608066. DOI: 10.1189/jlb.4MR0316-102R. View

18.

Pang X, He X, Qiu Z, Zhang H, Xie R, Liu Z . Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct Target Ther. 2023; 8(1):1. PMC: 9805914. DOI: 10.1038/s41392-022-01259-6. View

19.

Zhao P, Sui B, Liu N, Lv Y, Zheng C, Lu Y . Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. Aging Cell. 2017; 16(5):1083-1093. PMC: 5595695. DOI: 10.1111/acel.12635. View

20.

Zhang X, Jiang Y, Huang Q, Wu Z, Pu H, Xu Z . Exosomes derived from adipose-derived stem cells overexpressing glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia. Stem Cell Res Ther. 2021; 12(1):403. PMC: 8281719. DOI: 10.1186/s13287-021-02475-7. View