Adipose Mesenchymal Stem Cell Metabolites Oral Gel Enhance Pro-Angiogenic Factors Expression, Angiogenesis, and Clinical Outcome of Oral Ulcer Rat Model

Abstract

Objective Enhancing wound healing capacity is one of the main principles in oral ulcer management. Efficient oral ulcer management will accelerate clinical symptom amelioration and prevent complications. Adipose mesenchymal stem cell metabolites (AdMSCM), a novel biological product, contains a plethora of bioactive mediators that can induce a series of processes in wound healing. This study will analyze the clinical outcome, angiogenesis, and expression of FGF-2 and VEGFA in the oral ulcer rat model after AdMSCM oral gel application.

Materials and Methods Twenty healthy male Wistar rats (Rattus novergicus) were used to create oral ulcer animal models. AdMSCM oral gel treatment was performed three times daily for 3 and 7 days. Clinical outcome was assessed by measuring the major diameter of the ulcer; the angiogenesis was evaluated through histological assessment; the expression of VEGFA and FGF-2 was assessed using the immunohistochemistry method.

Statistical Analysis This study uses parametric comparative analysis using one-way analysis of variance (ANOVA) and post-hoc Tukey's HSD test

Results The application of AdMSCM oral gel in an oral ulcer rat model significantly enhanced the clinical outcome (p < 0.05). In addition, similar results were shown in the histologic assessment of angiogenesis and supported by the significant increase of VEGFA and FGF-2 expression.

Conclusions AdMSCM oral gel accelerates oral ulcer healing processes, proven by the enhancement of angiogenesis, pro-angiogenic factors expression, and clinical outcomes.

Keywords

oral ulcer - regenerative medicine - mesenchymal stem cell - dentistry

Publication History

Article published online:
24 March 2023

• References

• 1 Glick M. ed. Burket's Oral Medicine. 12th ed.. People's Medical Publishing House USA; 2015
• 2 Larjava H. ed. Oral Wound Healing: Cell Biology and Clinical Management. Wiley-Blackwell; 2012
• 3 Farah CS. Contemporary Oral Medicine: A Comprehensive Approach to Clinical Practice. Springer Berlin Heidelberg; 2019
• 4 Johnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care (New Rochelle) 2014; 3 (10) 647-661 DOI: 10.1089/wound.2013.0517.
• 5 Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 2016; 73 (20) 3861-3885 DOI: 10.1007/s00018-016-2268-0.
• 6 Bosanquet DC, Rangaraj A, Richards AJ, Riddell A, Saravolac VM, Harding KG. Topical steroids for chronic wounds displaying abnormal inflammation. Ann R Coll Surg Engl 2013; 95 (04) 291-296 . Doi: 10.1308/003588413 × 13629960045634
• 7 Karavana Hizarcioğlu SY, Sezer B, Güneri P. et al. Efficacy of topical benzydamine hydrochloride gel on oral mucosal ulcers: an in vivo animal study. Int J Oral Maxillofac Surg 2011; 40 (09) 973-978 DOI: 10.1016/j.ijom.2011.02.034.
• 8 Bunnell BA. Adipose tissue-derived mesenchymal stem cells. Cells 2021; 10 (12) 3433 DOI: 10.3390/cells10123433.
• 9 Ahangar P, Mills SJ, Cowin AJ. Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Int J Mol Sci 2020; 21 (19) 7038 DOI: 10.3390/ijms21197038.
• 10 Park SR, Kim JW, Jun HS, Roh JY, Lee HY, Hong IS. Stem cell secretome and its effect on cellular mechanisms relevant to wound healing. Mol Ther 2018; 26 (02) 606-617 DOI: 10.1016/j.ymthe.2017.09.023.
• 11 Ajit A, Ambika GopalankuttyI. Adipose-derived stem cell secretome as a cell-free product for cutaneous wound healing. Biotech 2021; 11 (09) 413
• 12 Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Gonçalves RM. Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning. Front Immunol 2018; 9: 2837 DOI: 10.3389/fimmu.2018.02837.
• 13 Nugraha AP, Susilowati H, Hendrianto E. et al; Purwati. Medicinal signaling cells metabolite oral based as a potential biocompatible biomaterial accelerating oral ulcer healing (in vitro study). Eur J Dent 2019; 13 (03) 432-436 DOI: 10.1055/s-0039-1693923.
• 14 Silva PGB, de Codes ÉBB, Freitas MO, Martins JOL, Alves APNN, Sousa FB. Experimental model of oral ulcer in mice: comparing wound healing in three immunologically distinct animal lines. J Oral Maxillofac Pathol 2018; 22 (03) 444 DOI: 10.4103/jomfp.JOMFP_144_17.
• 15 Gonzalez Ade O, Costa TF, Andrade Zde A, Medrado ARAP. Wound healing - A literature review. An Bras Dermatol. 2016; 91 (05) 614-620 DOI: 10.1590/abd1806-4841.20164741.
• 16 Politis C, Schoenaers J, Jacobs R, Agbaje JO. Wound healing problems in the mouth. Front Physiol 2016; 7: 507 DOI: 10.3389/fphys.2016.00507.
• 17 Shields AM, Panayi GS, Corrigall VM. Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?. Clin Exp Immunol 2011; 165 (03) 292-300 DOI: 10.1111/j.1365-2249.2011.04433.x.
• 18 Holthaus M, Santhakumar N, Wahlers T, Paunel-Görgülü A. The secretome of preconditioned mesenchymal stem cells drives polarization and reprogramming of M2a macrophages toward an IL-10-producing phenotype. Int J Mol Sci 2022; 23 (08) 4104 DOI: 10.3390/ijms23084104.
• 19 Mitchell R, Mellows B, Sheard J. et al. Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins. Stem Cell Res Ther 2019; 10 (01) 116 DOI: 10.1186/s13287-019-1213-1.
• 20 Zriek F, Di Battista JA, Alaaeddine N. Mesenchymal stromal cell secretome: immunomodulation, tissue repair and effects on neurodegenerative conditions. Curr Stem Cell Res Ther 2021; 16 (06) 656-669
• 21 Borges TJ, Wieten L, van Herwijnen MJC. et al. The anti-inflammatory mechanisms of Hsp70. Front Immunol 2012; 3: 95 DOI: 10.3389/fimmu.2012.00095.
• 22 Soliman AM, Das S, Abd Ghafar N, Teoh SL. Role of microRNA in proliferation phase of wound healing. Front Genet 2018; 9: 38
• 23 Jiang Y, Xu X, Xiao L, Wang L, Qiang S. The role of microRNA in the inflammatory response of wound healing. Front Immunol 2022; 13: 852419
• 24 Jiang CM, Liu J, Zhao JY. et al. Effects of hypoxia on the immunomodulatory properties of human gingiva-derived mesenchymal stem cells. J Dent Res 2015; 94 (01) 69-77 DOI: 10.1177/0022034514557671.
• 25 Demidova-Rice TN, Durham JT, Herman IM. Wound healing angiogenesis: innovations and challenges in acute and chronic wound healing. Adv Wound Care (New Rochelle) 2012; 1 (01) 17-22 DOI: 10.1089/wound.2011.0308.
• 26 Zimna A, Kurpisz M. Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. BioMed Res Int 2015; 2015: 549412 DOI: 10.1155/2015/549412.
• 27 Sunarto H, Trisnadi S, Putra A, Sa'dyah N, Tjipta A. The role of hypoxic mesenchymal stem cells conditioned medium in increasing vascular endothelial growth factors (VEGF) levels and collagen synthesis to accelerate wound healing. Indones J Cancer Chemoprevent 2020; 11 (03) 134-143
• 28 Farooq M, Khan AW, Kim MS, Choi S. The role of fibroblast growth factor (FGF) signaling in tissue repair and regeneration. Cells 2021; 10 (11) 3242 DOI: 10.3390/cells10113242.
• 29 Makino T, Jinnin M, Muchemwa FC. et al. Basic fibroblast growth factor stimulates the proliferation of human dermal fibroblasts via the ERK1/2 and JNK pathways. Br J Dermatol 2010; 162 (04) 717-723 DOI: 10.1111/j.1365-2133.2009.09581.x.
• 30 Viola A, Munari F, Sánchez-Rodríguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol 2019; 10: 1462
• 31 Arundina I, Diyatri I, Kusumaningsih T, Surboyo MDC, Monica E, Afanda NM. The role of rice hull liquid smoke in the traumatic ulcer healing. Eur J Dent 2021; 15 (01) 33-38 DOI: 10.1055/s-0040-1714445.
• 32 Kim SY, Nair MG. Macrophages in wound healing: activation and plasticity. Immunol Cell Biol 2019; 97 (03) 258-267 DOI: 10.1111/imcb.12236.