ISSN 2407-2230 | E-ISSN 1907-3062 | Universa Medicina content is searchable on DOAJ, Google Scholar, and OAI

Tumor necrosis factor-α-activated mesenchymal stem cells accelerate wound healing through vascular endothelial growth factor regulation in rats

Aditya Nugraha, Agung Putra
Submission date: Friday, 27 April 2018
Published date: Tuesday, 24 July 2018


Wounds are areas of physical or thermal damage of the epithelial layer of skin or mucosa. The wound healing process consists of hemostasis, inflammation, proliferation, and remodeling. Mesenchymal stem cells (MSCs) play a role in wound healing by suppressing potent pro-inflammatory molecules, such as tumor necrosis factor-α (TNF-α), leading to macrophage polarization from the pro-inflammatory type to the pro-regeneration type characterized by increasing vascular endothelial growth factor (VEGF) production. MSCs are able to increase VEGF level in-vivo correlated with collagen synthesis. The objective of this study was to assess the role of TNF-α-activated MSCs on VEGF in rat wounds.

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 one control (K) and three treatment groups (P) (activated MSCs at doses of 3x105, 6x105, and 12x105 cells, respectively). The measurement of VEGF levels was done using ELISA assay while the collagen analysis was performed by light microscopy. One way ANOVA and Post Hoc LSD were used to analyze the data.

The results showed a significant increase in VEGF levels (p <0.05) on day 3 and then a significant decrease on day 5 along with a significant increase in the amount of collagen on day 7 (p<0.05).

This study demonstrated that TNF-α-activated MSCs were able to regulate VEGF levels and collagen synthesis in wound healing in rats. The molecular mechanism by which TNF-α-activated MSCs stimulate cutaneous wound healing should be clarified further.


Mesenchymal stem cells; tumor necrosis factor-α; vascular endothelial growth factor; collagen; rats

Full Text:



Landen NX, Li D, Stahle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 2016;73:3861–85. doi: 10.1007/s00018-016-2268-0.

Nuschke A. Activity of mesenchymal stem cells in therapies for chronic skin wound healing. Organogenesis 2014;10:29–37. doi: 10.4161/org.27405.

Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res 2012;49:35–43.

Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: Molecular and cellular mechanisms. J Invest Dermatol 2007;127:514–25. doi:10.1038/sj.jid.5700701.

Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res 2015;2015:1–20. doi: 10.1155/2015/394917.

Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–7. doi: 10.1080/14653240600855905.

Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant 2011; 20:5-14. doi: 10.3727/096368910X.

Prockop DJ, Youn Oh J. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther 2012;20:14–20. doi:10.1038/mt.2011.211/nature06264.

Kwon YW, Heo SC, Jeong GO, et al. Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis. Biochim Biophys Acta - Mol Basis Dis 2013; 1832:2136-44. doi: 10.1016/j.bbadis.2013.08.002.

Sabio G, Davis RJ. TNF and MAP kinase signaling pathways. Semin Immunol 2014; 26:237–45. doi:10.1016/j.smim.2014.02.009.

Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity 2010;32:593–604. doi: 10.1016/j.immuni.2010.05.007.

Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007 110:3499-506. DOI:,9–506.

Lee S, Szilagyi E, Chen L, et al. Activated mesenchymal stem cells increase wound tensile strength in aged mouse model via macrophages. J Surg Res 2013;181:20–4. doi:10.1016/j.jss.2012.05.040.

Crisostomo PR, Wang Y, Markel TA, et al. Human mesenchymal stem cells stimulated by TNF-α, LPS, or hypoxia produce growth factors by an NFκB- but not JNK-dependent mechanism. AJP Cell Physiol 2008;294:C675–82. doi :10.1152/ajpcell.00437.2007.

Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A, LeRoux MA. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med 2012;1:142–9. doi: 10.5966/sctm.2011-0018.

Putra A, Rahmalita A, Tarra Y, et al. The effect of mesenchymal stem cells on the endothelial cells of diabetic mice. In: Proceedings of the 4th Bandung International Biomolecular Medicine Conference (BIBMC) and the 2nd Asean Congress on Medical Biotechnology and Molecular Biosciences (ACMM), Bandung, West Java, Indonesia, 4-6 October 2016.p.57-60.

Deshpande S, James AW, Blougha J, et al. Reconciling the effects of inflammatory cytokines on mesenchymal cell osteogenic differentiation. J Surg Res 2013 ;185:278-85. doi: 10.1016/j.jss.2013.06.063.

Bernardo ME, Fibbe WE. Review mesenchymal stromal cells: sensors and switchers of inflammation. Stem Cell 2013;13:392–402. doi: 10.1016/j.stem.2013.09.006.

Prockop DJ. Modulation of the process by mesenchymal stem / stromal cells. Matrix Biol 2016;51:7–13. doi:10.1016/j.matbio.2016.01.010.

Liang Y, Brekken RA, Hyder SM. Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 2006;13:905–19.

Bao P, Kodra A, Tomic-Canic M, et al. J Surg Res 2009;153:347–58. doi: 10.1016/j.jss.2008.04.023.

Barron L, Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. Am J Physiol Gastrointest Liver Physiol 2011;300:G723-8. doi: 10.1152/ajpgi.00414.2010.

Wright EJ, Hodson NW, Sherratt MJ, et al. Combined MSC and GLP-1 therapy modulates collagen remodeling and apoptosis following myocardial infarction. Stem Cells Int 2016;2016. Article ID 7357096, 12 pages.

Bauer SM, Bauer RJ, Liu ZJ, et al. Vascular endothelial growth factor-C promotes vasculogenesis, angiogenesis, and collagen constriction in three-dimensional collagen gels. J Vasc Surg 2005;41:699–707.


  • There are currently no refbacks.

Copyright (c) 2018 Universa Medicina

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Creative Commons License
Universa Medicina by Faculty of Medicine, Trisakti University is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Based on a work at