Shadi Mehrzad Sepideh sadat Hosseini Madjid Momeni-Moghaddam Moien Farshchian Halimeh Hassanzadeh Mahdi Mirahmadi Fatemeh Sadeghifar Hamid Reza Bidkhori


     Oxidative stress occurs as a result of breaking down the balance between oxidants (e.g., reactive oxygen species (ROS)) and antioxidants in cells. Several studies have shown that there is a close relationship between oxidative stress and inflammation at the sites of injury. Mesenchymal stem cells (MSCs) are exposed to endogenous and exogenous oxidants generated during their ex vivo expansion or following in vivo transplantation. α-tocopherol (vitamin E) is a fat-soluble compound known for its anti-oxidant and anti-inflammatory properties. In many studies, the immunomodulatory effects of vitamin E have been observed in vivo. This study aimed to determine whether pretreatment of MSCs with antioxidants like vitamin E, will enhance the anti-inflammatory and immunomodulatory properties of these cells. For this purpose, adipose-derived MSCs (ASCs) were treated with vitamin E (600 μM) for 48 h. Quantitative PCR (qPCR) experiments were performed to evaluate the expression of genes related to inflammation (IL-1β, IL-6, IL-17, IL-10) or immunomodulation (TSG-6, COX-2, TDO2, TGF-β1). Results indicated that vitamin E significantly increased the expression of COX-2, TSG-6, and IL-1β genes at the mRNA level compared with the control group, while it significantly decreased IL-6 and TGF-β expressions. No effect was observed for IL-17, IL-10, and TDO2 genes. These results suggest that in vitro preconditioning of ASCs with vitamin E may allow the cells to improve their anti-inflammatory and immunoregulatory capacities. Vitamin E pretreatment could lead to the improvement of their therapeutic abilities in conditions that are influenced by oxidative stress.

Article Details


Mesenchymal stem cells, Vitamin E, Immunomodulation, Oxidative stress, Preconditioning

Azzi A. (2007) Molecular mechanism of α-tocopherol action. Free Radical Biology and Medicine 43:16-21.

Azzi A. (2018) Many tocopherols, one vitamin E. Molecular Aspects of Medicine 61:92-103.

Baer P. C., Overath J. M., Urbschat A., Schubert R., Koch B., Bohn A. A. and Geiger H. (2018) Effect of different preconditioning regimens on the expression profile of murine adipose-derived stromal/stem cells. International Journal of Molecular Sciences 19:1719.

Barnes T. C., Anderson M. E. and Moots R. J. (2011) The many faces of interleukin-6: the role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis. International Journal of Rheumatology.

Barrows I. R., Ramezani A. and Raj D. S. (2019) Inflammation, Immunity, and Oxidative Stress in Hypertension—Partners in Crime? Advances in Chronic Kidney Disease 26:122-130.

Behl C., Davis J., Lesley R., and Schubert D. (1994) Hydrogen peroxide mediates amyloid β protein toxicity. Cell 77:817-827.

Ben-Zwi M., Petrou P., Halimi M., Karussis D. and Kassis I. (2019) Neuralized mesenchymal stem cells (NMSC) exhibit phenotypical, and biological evidence of neuronal transdifferentiation and suppress EAE more effectively than unmodified MSC. Immunology Letters 212:6-13.

Biswas S. K. (2016) Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxidative Medicine and Cellular Longevity.

Denu R. A. and Hematti P. (2016) Effects of oxidative stress on mesenchymal stem cell biology. Oxidative Medicine and Cellular Longevity.

Devine S. M., Bartholomew A. M., Mahmud N., Nelson M., Patil S., Hardy W., Sturgeon C., Hewett T., Chung T. and Stock W. (2001) Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Experimental hematology 29:244-255.

Droge W. (2002) Free radicals in the physiological control of cell function. Physiological Reviews 82:47-95.

Francis E., Kearney L. and Clover J. (2019) The effects of stem cells on burn wounds: a review. International Journal of Burns and Trauma 9:1.

Hu C. and Li L. (2018) Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. Journal of Cellular and Molecular Medicine 22:1428-1442.

Kelly R. P., Poo Yeo K., Isaac H. B., Lee C.-Y. J., Huang S. H., Teng L., Halliwell B. and Wise S. D. (2008) Lack of effect of acute oral ingestion of vitamin C on oxidative stress, arterial stiffness or blood pressure in healthy subjects. Free Radical Research 42:514-522.

Kihara H., Konno S. and Fujioka T. (2019) Alpha-Tocopherol Ameliorates Experimental Autoimmune Neuritis (P1. 2-089). AAN Enterprises.

Lee G. Y. and Han S. N. (2018) The role of vitamin E in immunity. Nutrients 10:1614.

Libby P. (2017) Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. Journal of the American College of Cardiology 70:2278-2289.

Linares G. R., Chiu C.-T., Scheuing L., Leng Y., Liao H.-M., Maric D. and Chuang D.-M. (2016) Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease. Experimental Neurology 281:81-92.

Lingappan K. (2018) NF-κB in oxidative stress. Current Opinion in Toxicology 7:81-86.

Lu L. Y., Loi F., Nathan K., Lin T. h., Pajarinen J., Gibon E., Nabeshima A., Cordova L., Jämsen E. and Yao Z. (2017) Pro-inflammatory M1 macrophages promote Osteogenesis by mesenchymal stem cells via the COX-2prostaglandin E2 pathway. Journal of Orthopaedic Research 35:2378-2385.

Mahmood L. A., Al Saadi R. and Matthews L. (2018) Dietary and antioxidant therapy for autistic children: Does it really work? Archives of Medicine and Health Sciences 6:73.

Mariathasan S., Turley S. J., Nickles D., Castiglioni A., Yuen K., Wang Y., Kadel III E. E., Koeppen H., Astarita J. L. and Cubas R. (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544.

Mishra G., Malik N., Paul A., Wadsworth M. and Bolton-Smith C. (2003) Childhood and adult dietary vitamin E intake and cardiovascular risk factors in mid-life in the 1946 British Birth Cohort. European Journal of Clinical Nutrition 57:1418-1425.

Naderi Meshkin H., Matin M. M., Heirani,Tabasi A., Mirahmadi M., Irfan-Maqsood M., Edalatmanesh M. A., Shahriyari M., Ahmadiankia N., Moussavi N. S. and Bidkhori H. R. (2016) Injectable hydrogel delivery plus preconditioning of mesenchymal stem cells: exploitation of SDF-1/CXCR4 axis toward enhancing the efficacy of stem cells' homing. Cell Biology International 40:730-741.

Németh K., Leelahavanichkul A., Yuen P. S., Mayer B., Parmelee A., Doi K., Robey P. G., Leelahavanichkul K., Koller B. H. and Brown J. M. (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E 2–dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine 15:42.

Palomo J., Dietrich D., Martin P., Palmer G. and Gabay C. (2015) The interleukin (IL)-1 cytokine family–Balance between agonists and antagonists in inflammatory diseases. Cytokine 76:25-37.

Pittenger M. F. and Martin B. J. (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circulation Research 95:9-20.

Rad F., Ghorbani M., Roushandeh A. M. and Roudkenar M. H. (2019) Mesenchymal stem cell-based therapy for autoimmune diseases: emerging roles of extracellular vesicles. Molecular Biology Reports 46:1533-1549.

Roddy G. W., Oh J. Y., Lee R. H., Bartosh T. J., Ylostalo J., Coble K., Rosa R. H., Jr. and Prockop D.J. (2011) Action at a distance: systemicallyadministered adult stem/progenitor cells (MSCs)reduce inflammatory damage to the cornea withoutengraftment and primarily by secretion of TNF-alpha stimulated gene/protein 6. Stem Cells29:1572-1579.

Rodriguez L. A., Mohammadipoor A., Alvarado L., Kamucheka R. M., Asher A. M., Cancio L. C. and Antebi B. (2019) Preconditioning in an Inflammatory Milieu Augments the Immunotherapeutic Function of Mesenchymal Stromal Cells. Cells 8:462.

Sangiorgi B., De Freitas H. T., Schiavinato J. L. D. S., Leão V., Haddad R., Orellana M. D., Faça V. M., Ferreira G. A., Covas D. T. and Zago M. A. (2016) DSP30 enhances the immunosuppressive properties of mesenchymal stromal cells and protects their suppressive potential from lipopolysaccharide effects: a potential role of adenosine. Cytotherapy 18:846-859.

Saxena A., Sonowal H. and Ramana K. V. (2019) Transcriptional Factor Modulation by Lipid Peroxidation-Derived Aldehydes. In The Molecular Nutrition of Fats. Elsevier. 419-431.

Schaefer R., Spohn G. and Baer P. C. (2016) Mesenchymal stem/stromal cells in regenerative medicine: can preconditioning strategies improve therapeutic efficacy. Transfusion Medicine and Hemotherapy 43:256-267.

Schaper F. and Rose-John S. (2015) Interleukin-6: biology, signaling and strategies of blockade. Cytokine & growth factor reviews 26:475-487.

Schieber M. and Chandel N. S. (2014) ROS function in redox signaling and oxidative stress. Current biology 24:R453-R462.

Shangguan L., Ti X., Krause U., Hai B., Zhao Y., Yang Z. and Liu F. (2012) Inhibition of TGF‐β/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma‐associated fibroblasts and abolishes their protumor effects. Stem cells 30:2810-2819.

Silva L. H., Antunes M. A., Dos Santos C. C., Weiss D. J., Cruz F. F. and Rocco P. R. (2018) Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases. Stem Cell Research & Therapy 9:45.

Tahan G., Aytac E., Aytekin H., Gunduz F., Dogusoy G., Aydin S., Tahan V. and Uzun H. (2011) Vitamin E has a dual effect of anti-inflammatory and antioxidant activities in acetic acid-induced ulcerative colitis in rats. Canadian Journal of Surgery 54:333.

Tanaka T., Narazaki M. and Kishimoto T. (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspectives in Biology 6:a016295.

Tang J., Xiong J., Wu T., Tang Z., Ding G., Zhang C., Wang S. and Liu Y. (2014) Aspirin treatment improved mesenchymal stem cell immunomodulatory properties via the 15d-PGJ2/PPARγ/TGF-β1 pathway. Stem cells and Development 23:2093-2103.

Wang N., Li Q., Zhang L., Lin H., Hu J., Li D., Shi S., Cui S., Zhou J., Ji J., Wan J., Cai G. and Chen X.(2012) Mesenchymal stem cells attenuateperitoneal injury through secretion of TSG-6. PLoSOne 7:e43768.

Wei X., Yang X., Han Z.-p., Qu F.-f., Shao L. and Shi Y.-f. (2013) Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacologica Sinica 34:747-754.

Wisel S., Khan M., Kuppusamy M. L., Mohan I. K., Chacko S. M., Rivera B. K., Sun B. C., Hideg K.and Kuppusamy P. (2009) Pharmacologicalpreconditioning of mesenchymal stem cells withtrimetazidine (1-[2, 3, 4-trimethoxybenzyl]piperazine) protects hypoxic cells against oxidativestress and enhances recovery of myocardialfunction in infarcted heart through Bcl-2expression. Journal of Pharmacology andExperimental Therapeutics 329:543-550.

Xue H., Ren H., Zhang L., Sun X., Wang W., Zhang S., Zhao J. and Ming L. (2016) Alpha-tocopherol ameliorates experimental autoimmune encephalomyelitis through the regulation of Th1 cells. Iranian Journal of Basic Medical Sciences 19:561.

Yang S.-R., Park J.-R. and Kang K.-S. (2015) Reactive oxygen species in mesenchymal stem cell aging: implication to lung diseases. Oxidative Medicine and Cellular Longevity 2015.

Yuan T., Yang T., Chen H., Fu D., Hu Y., Wang J., Yuan Q., Yu H., Xu W. and Xie X. (2019) New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biology 20:247-260.

Yun C. W. and Lee S. H. (2019) Enhancement of functionality and therapeutic efficacy of cell-based therapy using mesenchymal stem cells for cardiovascular disease. International Journal of Molecular Sciences 20:982.

Zhao L., Han F., Wang J. and Chen J. (2019) Current understanding of the administration of mesenchymal stem cells in acute kidney injury to chronic kidney disease transition: a review with a focus on preclinical models. Stem Cell Research & Therapy 10:385.

Zingg J.-M. (2015) Vitamin E: a role in signal transduction. Annual Review of Nutrition 35:135-173.
How to Cite
MehrzadS., HosseiniS. sadat, Momeni-MoghaddamM., FarshchianM., HassanzadehH., MirahmadiM., SadeghifarF., & BidkhoriH. R. (2020). Vitamin E Pretreatment of Mesenchymal Stem Cells: The Interplay of Oxidative Stress and Inflammation. Journal of Cell and Molecular Research, 11(2), 99-107. https://doi.org/10.22067/jcmr.v11i2.85668
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