Adipose mesenchymal stem cell-derived exosome attenuates radiation-induced oral mucositis

doi:10.12307/2025.040

Abstract

Abstract:

BACKGROUND: Radiotherapy for head and neck tumors is very likely to cause radiation-induced oral mucositis, which seriously affects the health of patients and the treatment plan of tumors. Mesenchymal stem cells have shown therapeutic potential in many diseases, and exosomes are one of the important factors for their function. At present, there is no application of adipose mesenchymal stem cell-derived exosomes in the study of radiation-induced oral mucositis.

OBJECTIVE: To investigate the role of adipose mesenchymal stem cell-derived exosomes in radiation-induced oral mucositis.

METHODS: Adipose mesenchymal stem cells and adipose mesenchymal stem cell-derived exosomes were extracted and identified. In vitro model of radiationinduced oral mucositis was induced by radiating oral mucosal epithelial cells with 3 Gy X-ray. Adipose mesenchymal stem cells or adipose mesenchymal stem cell-derived exosomes were pretreated for 48 hours before modeling. The proliferation capacity of oral mucosal epithelial cells was detected by EdU assay and clonal formation assay. A mouse model of radiation-induced oral mucositis was constructed through 3 Gy X-ray radiation. Adipose mesenchymal stem cells and adipose mesenchymal stem cell-derived exosomes were injected into the tail vein of radiation-induced oral mucositis mice. Hematoxylin-eosin staining and immunohistochemistry were used to evaluate the inflammatory changes of oral mucosal epithelial tissue.

RESULTS AND CONCLUSION: (1) Compared with the control group, both adipose mesenchymal stem cells and adipose mesenchymal stem cell-derived exosomes promoted the formation of oral epithelial cell clones and increased the positive rate of EdU in oral epithelial cells. (2) Both adipose mesenchymal stem cells and adipose mesenchymal stem cell-derived exosomes alleviated the inflammation of oral mucosal epithelium of irradiated mice; CD45 positive cells decreased and PCNA positive cells increased in oral mucosal epithelium. It is concluded that adipose mesenchymal stem cell-derived exosomes promote the proliferation of oral mucosal epithelial cells and release oral mucosal inflammation in mice with radiation-induced oral mucositis.

Key words: radiation-induced oral mucositis, adipose-derived mesenchymal stem cell, exosome, head and neck tumor, radiation therapy, oral mucosa, inflammation, malignant tumor

CLC Number:

Li Yang, Fu Lili, Yang Jiantang. Adipose mesenchymal stem cell-derived exosome attenuates radiation-induced oral mucositis[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(1): 31-37.

Figures/Tables 2

References

[1] LY KL, LUO X, RAUB CB. Oral mucositts on a chip: modeling inductton by chemo- and radiatton treatments and recovery. Biofabricatton. 2022;15(1):10.1088/1758-5090/ac933b.

[2] MARIA OM, ELIOPOULOS N, MUANZA T. Radiatton-Induced Oral Mucositts. Front Oncol. 2017;7:89.

[3] RAO D, BEHZADI F, LE RT, et al. Radiatton Induced Mucositts: What the Radiologist Needs to Know. Curr Probl Diagn Radiol. 2021;50(6): 899-904.

[4] SUBEDI P, HUBER K, STERR C, et al. Towards unravelling biological mechanisms behind radiatton-induced oral mucositts via mass spectrometry-based proteomics. Front Oncol. 2023;13:1180642.

[5] NIKITAKI Z, MAVRAGANI IV, LASKARATOU DA, et al. Systemic mechanisms and effects of ionizing radiatton: A new ‘old’ paradigm of how the bystanders and distant can become the players. Semin Cancer Biol. 2016;37-38:77-95.

[6] GKANTAIFI A, VARDAS E, ALONGI F, et al. Radiatton-Induced Oral Mucositts in Head and Neck Cancer Pattents. Five Years Literature Review. Rev Recent Clin Trials. 2021;16(2):151-165.

[7] KIM HJ, KANG SU, LEE YS, et al. Protecttve Effects of N-Acetylcysteine against Radiatton-Induced Oral Mucositts In Vitro and In Vivo. Cancer Res Treat. 2020;52(4):1019-1030.

[8] LEE CT, GALLOWAY TJ. Pathogenesis and Amelioratton of RadiattonInduced Oral Mucositts. Curr Treat Opttons Oncol. 2022;23(3): 311-324.

[9] PULITO C, CRISTAUDO A, PORTA C, et al. Oral mucositts: the hidden side of cancer therapy. J Exp Clin Cancer Res. 2020;39(1):210.

[10] DAVY C, HEATHCOTE S. A systemattc review of interventtons to mittgate radiotherapy-induced oral mucositts in head and neck cancer pattents. Support Care Cancer. 2021;29(4):2187-2202.

[11] WANG H, ZHANG K, RUAN Z, et al. Correctton to: Probucol enhances the therapeuttc efffciency of mesenchymal stem cells in the treatment of erecttle dysfunctton in diabettc rats by prolonging their survival ttme via Nrf2 pathway. Stem Cell Res Ther. 2022;13(1):47.

[12] SHIN JY, LEE PH. Mesenchymal stem cells modulate misfolded α-synuclein in parkinsonian disorders: A multttarget disease-modifying strategy. Stem Cell Res. 2020;47:101908.

[13] WANG Y, FANG J, LIU B, et al. Reciprocal regulatton of mesenchymal stem cells and immune responses. Cell Stem Cell. 2022;29(11): 1515-1530.

[14] ANDRZEJEWSKA A, DABROWSKA S, LUKOMSKA B, et al. Mesenchymal Stem Cells for Neurological Disorders. Adv Sci (Weinh). 2021;8(7): 2002944.

[15] XU L, JI H, JIANG Y, et al. Exosomes Derived From CircAkap7-Modiffed Adipose-Derived Mesenchymal Stem Cells Protect Against Cerebral Ischemic Injury. Front Cell Dev Biol. 2020;8:569977.

[16] HAN Y, YANG J, FANG J, et al. The secretton proffle of mesenchymal stem cells and potenttal applicattons in treattng human diseases. Signal Transduct Target Ther. 2022;7(1):92.

[17] OGAY V, SEKENOVA A, LI Y, et al. The Therapeuttc Potenttal of Mesenchymal Stem Cells in the Treatment of Atherosclerosis. Curr Stem Cell Res Ther. 2021;16(7):897-913.

[18] VAN BALKOM BWM, GREMMELS H, GIEBEL B, et al. Proteomic Signature of Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles. Proteomics. 2019;19(1-2):e1800163.

[19] SHANG Y, WANG Q, LI J, et al. Zirconia Nanoparttcles Induce HeLa Cell Death Through Mitochondrial Apoptosis and Autophagy Pathways Mediated by ROS. Front Chem. 2021;9:522708.

[20] DING X, NIE Z, SHE Z, et al. The Regulatton of ROS- and BECN1- Mediated Autophagy by Human Telomerase Reverse Transcriptase in Glioblastoma. Oxid Med Cell Longev. 2021;2021:6636510.

[21] KMA L, BARUAH TJ. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol Appl Biochem. 2022;69(1): 248-264.

[22] SANKAR V, XU Y. Oral Complicattons from Oropharyngeal Cancer Therapy. Cancers (Basel). 2023;15(18):4548.

[23] ELTING LS, COOKSLEY CD, CHAMBERS MS, et al. Risk, outcomes, and costs of radiatton-induced oral mucositts among pattents with headand-neck malignancies. Int J Radiat Oncol Biol Phys. 2007;68(4): 1110-1120.

[24] LIU S, ZHAO Q, ZHENG Z, et al. Status of Treatment and Prophylaxis for Radiatton-Induced Oral Mucositts in Pattents With Head and Neck Cancer. Front Oncol. 2021;11:642575.

[25] SONIS ST. Precision medicine for risk predictton of oral complicattons of cancer therapy-The example of oral mucositts in pattents receiving radiatton therapy for cancers of the head and neck. Front Oral Health. 2022;3:917860.

[26] CHEN G, WANG M, RUAN Z, et al. Mesenchymal stem cell-derived exosomal miR-143-3p suppresses myocardial ischemia-reperfusion injury by regulattng autophagy. Life Sci. 2021;280:119742.

[27] TELI P, KALE V, VAIDYA A. Extracellular vesicles isolated from mesenchymal stromal cells primed with neurotrophic factors and signaling modiffers as potenttal therapeuttcs for neurodegenerattve diseases. Curr Res Transl Med. 2021;69(2):103286.

[28] LU X, BAO H, CUI L, et al. hUMSC transplantatton restores ovarian functton in POI rats by inhibittng autophagy of theca-intersttttal cells via the AMPK/mTOR signaling pathway. Stem Cell Res Ther. 2020; 11(1):268.

[29] LI T, GU J, YANG O, et al. Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miRNA-29c Decreases Cardiac Ischemia/Reperfusion Injury Through Inhibitton of Excessive Autophagy via the PTEN/Akt/mTOR Signaling Pathway. Circ J. 2020;84(8):1304-1311.

[30] MA CY, ZHAI Y, LI CT, et al. Translattng mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: Promises, problems and prospects. Med Res Rev. 2023. doi: 10.1002/ med.22002.

[31] ZHOU C, ZHANG B, YANG Y, et al. Stem cell-derived exosomes: emerging therapeuttc opportunittes for wound healing. Stem Cell Res Ther. 2023;14(1):107.

[32] ZOU J, YANG W, CUI W, et al. Therapeuttc potenttal and mechanisms of mesenchymal stem cell-derived exosomes as bioacttve materials in tendon-bone healing. J Nanobiotechnology. 2023;21(1):14.

[33] WANG L, HU L, ZHOU X, et al. Author Correctton: Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulattng extracellular matrix remodelling. Sci Rep. 2021; 11(1):3245.

[34] XU T, LIN Y, YU X, et al. Comparattve Effects of Exosomes and Ectosomes Isolated From Adipose-Derived Mesenchymal Stem Cells on Achilles Tendinopathy in a Rat Model. Am J Sports Med. 2022;50(10): 2740-2752.

[35] WANG X, JIAO Y, PAN Y, et al. Fetal Dermal Mesenchymal Stem CellDerived Exosomes Accelerate Cutaneous Wound Healing by Acttvattng Notch Signaling. Stem Cells Int. 2019;2019:2402916.

[36] VU NB, NGUYEN HT, PALUMBO R, et al. Stem cell-derived exosomes for wound healing: current status and promising directtons. Minerva Med. 2021;112(3):384-400.