The Role of Hypoxic Mesenchymal Stem Cells Conditioned Medium in Increasing Vascular Endothelial Growth Factors (VEGF) Levels and Collagen Synthesis to Accelerate Wound Healing
Abstract
Full-thickness wound are areas damage of skin associated with loss of epidermis and dermis. The wound healing mechanism consists proliferation, migration and remodeling. Hypoxic conditional medium of mesenchymal stem cells (HMSCs-CM) contains lots of soluble molecules, such as protein growth factor and cytokine anti-inflammation. The soluble molecule of HMSCs-CM plays a critical role in wound healing by upregulation of VEGF and collagen synthesis. The objective of this study was to evaluate the effect of HMSCs-CM on VEGF and collagen concentrations in rats with incised wounds. The methods of this study were an experimental animal study with post-test only control group design was performed involving 24 Wistar rats. The rats were randomized into four groups consisting of sham, control and two treatment groups (gel of HMSCs-CM at doses of 200 μL and 400 μL). The VEGF levels and collagen density were analyses using ELISA assay and Masson-trichome specific staining, respectively. One-way ANOVA and Post Hoc LSD were used to analyses the data. The results of this study showed that a VEGF levels was significant increased on day 6 with doses-dependent manner. Interestingly, the VEGF levels gradual decrease on day 9. In addition, the decreased of VEGF levels on day 9 in this study in line with our findings in which we found there was a trend in the decreased of collagen density, it indicated the completion of remodeling phase and there has been an acceleration in wound healing. This study demonstrated that HMSCs-CM were able to regulate VEGF levels and collagen synthesis in accelerate wound healing. The role of HMSCs-CM stimulate cutaneous wound healing should be clarified further.
Keywords: hypoxic conditional medium of mesenchymal stem cells (HMSCs-CM), vascular endothelial growth factor, collagen synthesis, paracrine factors
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Al-Qattan, M.M., Abd-Elwahed, M.M., Hawary, K., Arafah, M.M. and Shier, M.K., 2015, Myofibroblast expression in skin wounds is enhanced by collagen III suppression, BioMed Research International, 2015. CrossRef
Bao, P., Kodra, A., Tomic-Canic, M., Golinko, M. S., Ehrlich, H.P. and Brem, H., 2009, The Role of Vascular Endothelial Growth Factor in Wound Healing, Journal of Surgical Research, 153(2), 347–358. CrossRef
Bernardo, M.E. and Fibbe, W.E., 2013, Mesenchymal stromal cells: Sensors and switchers of inflammation, Cell Stem Cell, 13(4), 392–402. CrossRef
Eggenhofer, E., Benseler, V., Kroemer, A., Popp, F.C., Geissler, E.K., Schlitt, H. J., Baan, C.C., Dahlke, M.H. and Hoogduijn, M.J., 2012, Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion, Frontiers in Immunology, 3(SEP), 1–8. CrossRef
Eming, S.A., Martin, P. and Tomic-Canic, M., 2014, Wound Repair and Regeneration MechaniEming, S. A., Martin, P., & Tomic-Canic, M. (2014). Wound Repair and Regeneration Mechanisms, Science TransL Med, 322(265), 265sr6. CrossRef
Falanga, V., 2005, Wound healing and its impairment in the diabetic foot, Lancet, 366(9498), 1736–1743. CrossRef
Fu, X., Fang, L., Li, X., Cheng, B. and Sheng, Z., 2006, Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury, Wound Repair and Regeneration, 14(3), 325–335. CrossRef
Gibb, A.A., Lazaropoulos, M.P. and Elrod, J.W., 2020, Myofibroblasts and Fibrosis: Mitochondrial and Metabolic Control of Cellular Differentiation, Circulation Research, 427–447. CrossRef
Goodarzi, P., Alavi-Moghadam, S., Sarvari, M., Tayanloo Beik, A., Falahzadeh, K., Aghayan, H., Payab, M., Larijani, B., Gilany, K., Rahim, F., Adibi, H. and Arjmand, B., 2018, Adipose tissue-derived stromal cells for wound healing, Advances in Experimental Medicine and Biology, 1119, 133–149. CrossRef
Johnson, K.E. and Wilgus, T.A., 2014, Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair, Advances in Wound Care, 3(10), 647–661. CrossRef
Kuntardjo, N., Dharmana, E., Chodidjah, C., Nasihun, T. R. and Putra, A., 2019, TNF-α-Activated MSC-CM Topical Gel Effective in Increasing PDGF Level, Fibroblast Density, and Wound Healing Process Compared to Subcutaneous Injection Combination, Majalah Kedokteran Bandung, 51(1), 1–6. CrossRef
Lee, R.H., Pulin, A.A., Seo, M.J., Kota, D.J., Ylostalo, J., Larson, B.L., Semprun-prieto, L., Delafontaine, P. and Darwin, J., 2009, Intravenous hMSCs Improve Myocardial Infarction in Mice because Cells Embolized in Lung Are Activated to Secrete the Anti-inflammatory Protein TSG-6, CELL STEM CELL, 5(1), 54–63. CrossRef
Liang, Y., Brekken, R.A. and Hyder, S.M., 2006, Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones, Endocrine-Related Cancer, 13(3), 905–919. CrossRef
Lu, Y., Azad, N., Wang, L., Iyer, A.K.V., Castranova, V., Jiang, B.H. and Rojanasakul, Y., 2010, Phosphatidylinositol-3-kinase/Akt regulates bleomycin-induced fibroblast proliferation and collagen production, American Journal of Respiratory Cell and Molecular Biology, 42(4), 432–441. CrossRef
McFarlin, K., Gao, X., Liu, Y.B., Dulchavsky, D.S., Kwon, D., Arbab, A.S., Bansal, M., et al., 2006, Bone marrow-derived mesenchymal stromal cells accelerate wound healing in the rat, Wound Repair and Regeneration, 14(4), 471–478. CrossRef
Muhar, A. M., Putra, A., Warli, S. M. and Munir, D., 2019, Hypoxia-mesenchymal stem cells inhibit intra-peritoneal adhesions formation by upregulation of the il-10 expression, Open Access Macedonian Journal of Medical Sciences, 7(23), 3937–3943. CrossRef
Nugraha, A. and Putra, A., 2018, Tumor necrosis factor-α-activated mesenchymal stem cells accelerate wound healing through vascular endothelial growth factor regulation in rats, Universa Medicina, 37(2), 135. CrossRef
Putra, A., Antari, A.D., Kustiyah, A.R., Intan, Y.S.N., Sadyah, N.A.C., Wirawan, N., Astarina, S., et al., 2018, Mesenchymal stem cells accelerate liver regeneration in acute liver failure animal model, Biomedical Research and Therapy, 5(11), 2802–2810. CrossRef
Putra, A., Pertiwi, D., Milla, M.N., Indrayani, U. D., Jannah, D., Sahariyani, M., Trisnadi, S. and Wibowo, J.W., 2019, Hypoxia-preconditioned MSCs have superior effect in ameliorating renal function on acute renal failure animal model, Open Access Macedonian Journal of Medical Sciences, 7(3), 305–310. CrossRef
Quade, M., Münch, P., Lode, A., Duin, S., Vater, C., Gabrielyan, A., Rösen-Wolff, A. and Gelinsky, M., 2020, The Secretome of Hypoxia Conditioned hMSC Loaded in a Central Depot Induces Chemotaxis and Angiogenesis in a Biomimetic Mineralized Collagen Bone Replacement Material, Advanced Healthcare Materials, 9(2). CrossRef
Rong, X., Li, J., Yang, Y., Shi, L. and Jiang, T., 2019, Human fetal skin-derived stem cell secretome enhances radiation-induced skin injury therapeutic effects by promoting angiogenesis, Stem Cell Research and Therapy, 10(1), 1–11. CrossRef
Smiell, J.M., Wieman, T.J., Steed, D.L., Perry, B.H., Sampson, A.R. and Schwab, B.H., 1999, Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB)in patients with nonhealing, lower extremity diabetic ulcers: A combined analysis of four randomized studies, Wound Repair and Regeneration, 7(5), 335–346. CrossRef
Song, Y.S., Lee, H.J., Doo, S.H., Lee, S.J., Lim, I., Chang, K.T. and Kim, S.U., 2012, Mesenchymal stem cells overexpressing hepatocyte growth factor (HGF) inhibit collagen deposit and improve bladder function in rat model of bladder outlet obstruction, Cell Transplantation, 21(8), 1641–1650. CrossRef
Uranga, R.M., Katz, S. and Salvador, G.A., 2013, Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress, Journal of Biological Chemistry, 288(27), 19773–19784. CrossRef
Wang, N., Wu, Y., Zeng, N., Wang, H., Deng, P., Xu, Y., Feng, Y., et al., 2016, E2F1 Hinders Skin Wound Healing by Repressing Vascular Endothelial Growth Factor (VEGF) Expression, Neovascularization, and Macrophage Recruitment, PLoS ONE, 11(8), 1–10. CrossRef
Wise, L.M., Stuart, G.S., Real, N.C., Fleming, S.B., and Mercer, A.A., 2018, VEGF Receptor-2 Activation Mediated by VEGF-E Limits Scar Tissue Formation Following Cutaneous Injury, Advances in Wound Care, 7(8), 283–297. CrossRef
Wu, Y., Chen, L., Scott, P.G. and Tredget, E.E., 2007, Mesenchymal Stem Cells Enhance Wound Healing Through Differentiation and Angiogenesis, Stem Cells, 25(10), 2648–2659. CrossRef
Xia, X., Chiu, P.W.Y., Lam, P.K., Chin, W.C., Ng, E.K.W. and Lau, J.Y.W., 2018, Secretome from hypoxia-conditioned adipose-derived mesenchymal stem cells promotes the healing of gastric mucosal injury in a rodent model, Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(1), 178–188. CrossRef
Yustianingsih, V., Sumarawati, T. and Putra, A., 2019, Hypoxia enhances self-renewal properties and markers of mesenchymal stem cells, Universa Medicina, 38(3), 164. CrossRef
DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev11iss3pp134-143
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