Effects of Vitamin D3 Supplementation on the Expression of Interleukin-6 and Vascular Endothelial Growth Factor of Umbilical Cord-Derived Mesenchymal Stem Cells

Ariza Julia Paulina, Elmi Elmi, Nicko Pisceski Kusika Saputra, T Syarifah Dessi IS Assegaf, Dino Irawan, Fadhilla Maulany El Fajri, Maisarah Elfajri Putri, Sucitra Sucitra, Rahma Dhani, Arfianti Arfianti

Abstract

Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal ability, low immunogenicity, homing, and immunomodulatory function; thus, they had great potential in regenerative medicine. Preconditioning of MSCs cultures is known to enhance their immunomodulatory effects in various clinical applications. This study aimed to determine the effect of vitamin D3 supplementation on the viability and expression of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) mRNA in MSCs. Methods: Methods: MSCs were isolated from Wharton's jelly umbilical cord and were cultured using the explant method. MSCs at passage 3 were cultured on 6-well plates and were divided into four experimental groups: 1, 10, and 100 nM vitamin D3 supplementation groups and the control group (without vitamin D3 supplementation). After vitamin D3 supplementation for 24 h, viability was examined using the Cell Counting Kit 8 (CCK 8) assay, and IL-6 and VEGF mRNA expression was analyzed using quantitative polymerase chain reaction (qPCR). Data were analyzed using one-way ANOVA, and p-value < 0.05 was considered significant. Results: MSCs supplemented with vitamin D3 at concentrations of 1, 10, and 100 nM for 24 h showed increased viability. Findings indicated that supplementation with vitamin D3 1 nM for 24 h significantly decreased IL-6 expression, whereas supplementation of vitamin D3 10 and 100 nM for 24 h increased IL-6 expression compared to the control group, but the difference were not significant (p=0.1883). Supplementation with vitamin D3 at 10 nM for 24 h significantly decreased VEGF expression compared to that in the control group. Vitamin D3 preconditioning modulated IL-6 and VEGF mRNA expression in UC-MSCs, suggesting potential effects on inflammatory and angiogenic pathways. Conclusion: Vitamin D3 supplementation modulated IL-6 and VEGF expression in UC-MSCs in a dose-dependent, non-linear manner.

Keywords

Mesenchymal Stem Cells, Vitamin D3, IL-6, VEGF

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References

Huang Y, Wu Q, Tam PKH. Immunomodulatory mechanisms of mesenchymal stem cells and their potential clinical applications. Int J Mol Sci. 2022;23(17):10023.

Wei W, Ao Q, Wang X, Cao Y, Liu Y, Zheng SG, et al. Mesenchymal stem cell-derived exosomes: a promising biological tool in nanomedicine. Front Pharmacol. 2020;11:590470.

Macrin D, Joseph JP, Pillai AA, Devi A. Eminent sources of adult mesenchymal stem cells and their therapeutic imminence. Stem Cell Rev Rep. 2017;13(6):741–56.

Lee C, Kim M, Han J, Yoon M, Jung Y. Mesenchymal stem cells influence activation of hepatic stellate cells, and constitute a promising therapy for liver fibrosis. Biomedicines. 2021;9(11):1598.

François M, Romieu-Mourez R, Li M, Galipeau J. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther. 2012;20(1):187–95.

Li Y, Altemus J, Lightner AL. Mesenchymal stem cells and acellular products attenuate murine induced colitis. Stem Cell Res Ther. 2020;11(1):515.

Dorronsoro A, Lang V, Ferrin I, Fernández-Rueda J, Zabaleta L, Pérez-Ruiz E, et al. Intracellular role of IL-6 in mesenchymal stromal cell immunosuppression and proliferation. Sci Rep. 2020;10(1):21853.

Huang P, Zhang C, Delawary M, Korchak JA, Suda K, Zubair AC. Development and evaluation of IL-6 overexpressing mesenchymal stem cells (MSCs). J Tissue Eng Regen Med. 2022;16(3):244–53.

Viveiros MMH, Viveiros ME de M, Silva MG, Kaneno R, Avelino NP, Rainho CA, et al. Expression of inflammatory cytokines in mesenchymal stem cells derived from proximal humerus fractures. Stem Cell Investig. 2022;9:3.

Choy EH, De Benedetti F, Takeuchi T, Hashizume M, John MR, Kishimoto T. Translating IL-6 biology into effective treatments. Nat Rev Rheumatol. 2020;16(6):335–45.

Yang Y, Zhang Y, Xing X, Xu G, Lin X, Wang Y, et al. IL-6 translation is a therapeutic target of human cytokine release syndrome. J Exp Med. 2023;220(11):e20230577.

Kerkis I, Silva ÁP da, Araldi RP. The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions. Front Immunol. 2024;15.

Bieńko K, Leszcz M, Więckowska M, Białek J, Petniak A, Szymanowski R, et al. VEGF expression in umbilical cord MSC depends on the patient’s health, the week of pregnancy in which the delivery took place, and the body weight of the newborn - preliminary report. Stem Cells Cloning. 2023;16:5–18.

Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell. 2019;176(6):1248–64.

Konala VBR, Bhonde R, Pal R. Secretome studies of mesenchymal stromal cells (MSCs) isolated from three tissue sources reveal subtle differences in potency. In Vitro Cell Dev Biol Anim. 2020;56(9):689–700.

Birkenhauer E, Neethirajan S. A double-edged sword: The role of VEGF in wound repair and chemoattraction of opportunist pathogens. Int J Mol Sci. 2015;16(4):7159–72.

Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: Toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017;18(9):1852.

Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, et al. Stem cell-based therapy for human diseases. Signal Transduct Target Ther. 2022;7:272.

Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or future. Stem Cell Rev Rep. 2020;16(3):427–33.

Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci. 2020;77(14):2771–94.

Hu C, Li L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med. 2018;22(3):1428–42.

Hamden K, Carreau S, Jamoussi K, Miladi S, Lajmi S, Aloulou D, et al. 1Alpha,25 dihydroxyvitamin D3: therapeutic and preventive effects against oxidative stress, hepatic, pancreatic and renal injury in alloxan-induced diabetes in rats. J Nutr Sci Vitaminol (Tokyo). 2009;55(3):215–22.

Yuhendri VM, Pratiwi N, Paulina AJ, Ismawati I, Saputra NPK, Arfianti A. Vitamin D enhances migration but decreases gene expression of vascular endothelial growth factor and tumor necrosis factor-α in Wharton’s jelly mesenchymal stem cells. Indones J Med Lab Sci Technol. 2025;7(1):49–59.

Bandekar M, Maurya DK, Sharma D, Sandur SK. Preclinical studies and clinical prospects of Wharton’s jelly-derived MSC for treatment of acute radiation syndrome. Curr Stem Cell Rep. 2021;7(2):85–94.

Xiang D, Zou J, Zhu X, Chen X, Luo J, Kong L, et al. Physalin D attenuates hepatic stellate cell activation and liver fibrosis by blocking TGF-β/Smad and YAP signaling. Phytomedicine. 2020 Nov;78:153294.

Mathot F, Rbia N, Thaler R, Dietz AB, van Wijnen AJ, Bishop AT, et al. Gene expression profiles of human adipose-derived mesenchymal stem cells dynamically seeded on clinically available processed nerve allografts and collagen nerve guides. Neural Regen Res. 2021;16(8):1613–21.

Wang D, Wang S, Huang S, Zhang Z, Yuan X, Feng X, et al. Serum IFN-γ predicts the therapeutic effect of mesenchymal stem cells transplantation in systemic lupus erythematosus patients. Stem Cells Transl Med. 2017 Sep;6(9):1777–85.

Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WCW. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem Cells Int. 2016;2016:3924858.

Arfianti A, Ulfah, Hutabarat LS, Agnes Ivana G, Budiarti AD, Sahara NS, et al. Hipoxia modulates the secretion of growth factors of human umbilical cord-derived mesenchymal stem cells. Biomedicine (Taipei). 2023;13(3):49–56.

Chen H, Ji M, Ding Z, Yan Y. Vitamin D3-loaded calcium citrate/calcium sulfate composite cement with enhanced physicochemical properties, drug release, and cytocompatibility. J Biomater Appl. 2020;34(10):1343–54.

Vu AA, Bose S. Vitamin D3 release from traditionally and additively manufactured tricalcium phosphate bone tissue engineering scaffolds. Ann Biomed Eng. 2020;48(3):1025–33.

Yang CY, Chang PY, Chen JY, Wu BS, Yang AH, Lee OKS. Adipose-derived mesenchymal stem cells attenuate dialysis-induced peritoneal fibrosis by modulating macrophage polarization via interleukin-6. Stem Cell Res Ther. 2021;12(1):193.

Fierro FA, Magner N, Beegle J, Dahlenburg H, Logan White J, Zhou P, et al. Mesenchymal stem/stromal cells genetically engineered to produce vascular endothelial growth factor for revascularization in wound healing and ischemic conditions. Transfusion. 2019;59(S1):893–7.

DOI: https://doi.org/10.26891/JIK.v20i1.2026.50-58

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