Effect of Secretome-Hypoxia Mesenchymal Stem Cells on Regulating SOD and MMP-1 mRNA Expressions in Skin Hyperpigmentation Rats


  • Zukhiroh Zukhiroh Graduate Student of Biomedical Science Program, Faculty of Medicine, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
  • Agung Putra Departement of Postgraduate Biomedical Science, Faculty of Medicine, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Stem Cell and Cancer Research, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia https://orcid.org/0000-0003-4261-9437
  • Chodidjah Chodidjah Departement of Postgraduate Biomedical Science, Faculty of Medicine, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
  • Titiek Sumarawati Departement of Postgraduate Biomedical Science, Faculty of Medicine, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
  • Prasetyowati Subchan Departement of Postgraduate Biomedical Science, Faculty of Medicine, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
  • Setyo Trisnadi Departement of Postgraduate Biomedical Science, Faculty of Medicine, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
  • Nurul Hidayah Stem Cell and Cancer Research, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Graduated Student of Biotechnology Program, Graduate School, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Nur Dina Amalina Stem Cell and Cancer Research, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Pharmacy Study Program, Faculty of Mathematics and Natural Sciences, Universitas Negeri Semarang, Semarang, Indonesia




Secretome, Superoxide dismutase, Matrix metalloproteinases-1, Hyperpigmentation, qRT-PCR


BACKGROUND: Ultraviolet B (UVB) radiation is the main factor causing hyperpigmentation. MSC secretome contains bioactive soluble molecules such as cytokines and growth factors that can accelerate skin regeneration. However, the molecular role of the secretome in hyperpigmentation is still unclear.

AIM: This study aimed to determine the effect of secretome hypoxia mesenchymal stem cells (S-HMSC) gel on the expression of superoxide dismutase (SOD) and matrix metalloproteinases (MMP-1) genes in skin tissue of hyperpigmented rats induced by UVB light exposure.

MATERIALS AND METHODS: Experimental research with post-test only control group. The control, base gel, T1 and T2 groups were UVB irradiated 6 times in 14 days at 302 nm with an minimal erythema dose of 390 mJ/cm2, respectively, while sham group did not receive UVB exposure. T1 was given 100 uL of S-HMSC gel and T2 was given 200 uL of S-HMSC gel every day for 14 days, while base gel received base gel. On day 15, skin tissue was isolated and analyzed for SOD and MMP-1 expression using qRT-PCR.

RESULTS: The relative expression of the SOD gene in the treatment group (P1 = 0.47 ± 0.20, P2 = 1.22 ± 0.47) increased with increasing dose compared to the control group (UVB = 0.05 ± 0.01, Base gel = 0.05 ± 0.02). The relative expression of the MMP-1 gene in the treatment group (T1 = 5.82 ± 1.16, T2 = 2.86 ± 1.57) decreased with increasing dose compared to the control group (Control = 10.10 ± 2.31, and Base gel = 9.55 ± 1.29).

CONCLUSION: Administration of S-HMSC gel can increase SOD gene expression and decrease MMP-1 gene expression in skin tissue of hyperpigmented rats model induced by UVB light.


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Kim HY, Sah SK, Choi SS, Kim TY. Inhibitory effects of extracellular superoxide dismutase on ultraviolet B-induced melanogenesis in murine skin and melanocytes. Life Sci. 2018;210:201-8. https://doi.org/10.1016/j.lfs.2018.08.056 PMid:30145155 DOI: https://doi.org/10.1016/j.lfs.2018.08.056

Moon HR, Jung JM, Kim SY, Song Y, Chang SE. TGF-β3 suppresses melanogenesis in human melanocytes cocultured with UV-irradiated neighboring cells and human skin. J Dermatol Sci. 2020;99(2):100-8. https://doi.org/10.1016/j.jdermsci.2020.06.007 PMid:32620316 DOI: https://doi.org/10.1016/j.jdermsci.2020.06.007

Kwon KR, Alam MB, Park JH, Kim TH, Lee SH. Attenuation of UVB-induced photo-aging by polyphenolic-rich spatholobus suberectus stem extract via modulation of MAPK/AP-1/MMPs signaling in human keratinocytes. Nutrients. 2019;11(6):1341. https://doi.org/10.3390/nu11061341 PMid:31207929 DOI: https://doi.org/10.3390/nu11061341

Siebenga PS, van Amerongen G, Klaassen ES, de Kam ML, Rissmann R, Groeneveld GJ. The ultraviolet B inflammation model: Postinflammatory hyperpigmentation and validation of a reduced UVB exposure paradigm for inducing hyperalgesia in healthy subjects. Eur J Pain. 2019;23(5):874-83. https://doi.org/10.1002/ejp.1353 PMid:30597682 DOI: https://doi.org/10.1002/ejp.1353

Bahaloo M, Rezvani ME, Yazd EF, Mehrjerdi FZ, Davari MH, Roohbakhsh A, et al. Spectroscopic investigation on the interaction of DNA with superparamagnetic iron oxide nanoparticles doped with chromene via dopamine as cross linker. Iran J Basic Med Sci. 2020;23:594-9.

Halliday GM. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res. 2005;571(1-2):107-20. https://doi.org/10.1016/j.mrfmmm.2004.09.013 PMid:15748642 DOI: https://doi.org/10.1016/j.mrfmmm.2004.09.013

Cho BS, Lee J, Won Y, Duncan DI, Jin RC, Lee J, et al. Skin brightening efficacy of exosomes derived from human adipose tissue-derived stem/stromal cells: A prospective, split-face, randomized placebo-controlled study. Cosmetics. 2020;7(4):90. https://doi.org/10.3390/cosmetics7040090 DOI: https://doi.org/10.3390/cosmetics7040090

Zhou X, Du HH, Ni L, Ran J, Hu J, Yu J, et al. Nicotinamide mononucleotide combined with Lactobacillus fermentum TKSN041 reduces the photoaging damage in murine skin by activating AMPK signaling pathway. Front Pharmacol. 2021;12:643089. https://doi.org/10.3389/fphar.2021.643089 PMid:33841160 DOI: https://doi.org/10.3389/fphar.2021.643089

Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M. Role of matrix metalloproteinases in photoaging and photocarcinogenesis. Int J Mol Sci. 2016;17(6):868. https://doi.org/10.3390/ijms17060868 PMid:27271600 DOI: https://doi.org/10.3390/ijms17060868

Feng XX, Yu XT, Li WJ, Kong SZ, Liu YH, Zhang X, et al. Effects of topical application of Patchouli alcohol on the UV-induced skin photoaging in mice. Eur J Pharm Sci. 2014;63:113-23. https://doi.org/10.1016/j.ejps.2014.07.001 PMid:25033712 DOI: https://doi.org/10.1016/j.ejps.2014.07.001

Putra A, Alif I, Hamra N, Santosa O, Kustiyah AR, Muhar AM, Lukman K. MSC-released TGF-β regulate α-SMA expression of myofibroblast during wound healing. Journal of stem cells & regenerative medicine. 2020;16(2):73. https://doi.org/10.46582/ jsrm.1602011 DOI: https://doi.org/10.46582/jsrm.1602011

Balasubramanian S, Thej C, Walvekar A, Swamynathan P, Gupta PK, Seetharam RN, et al. Evaluation of the secretome profile and functional characteristics of human bone marrow mesenchymal stromal cells-derived conditioned medium suggest potential for skin rejuvenation. J Cosmet Dermatol Sci Appl. 2017;07(1):99-117. https://doi.org/10.4236/jcdsa.2017.71010 DOI: https://doi.org/10.4236/jcdsa.2017.71010

Gromolak S, Krawczenko A, Antończyk A, Buczak K, Kiełbowicz Z, Klimczak A. Biological characteristics and osteogenic differentiation of ovine bone marrow derived mesenchymal stem cells stimulated with FGF-2 and BMP- 2. Int J Mol Sci. 2020;21(24):9726. https://doi.org/10.3390/ijms21249726 PMid:33419255 DOI: https://doi.org/10.3390/ijms21249726

Kumar PL, Kandoi S, Misra R, Vijayalakshmi S, Rajagopal K, Verma RS. The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine. Cytokine Growth Factor Rev. 2019;46:1-9. https://doi.org/10.1016/j.cytogfr.2019.04.002 PMid:30954374 DOI: https://doi.org/10.1016/j.cytogfr.2019.04.002

Sevivas N, Teixeira FG, Portugal R, Araújo L, Carriço LF, Ferreira N, et al. Mesenchymal stem cell secretome: A Potential tool for the prevention of muscle degenerative changes associated with chronic rotator cuff tears. Am J Sports Med. 2017;45(1):179-88. https://doi.org/10.1177/0363546516657827 PMid:27501832 DOI: https://doi.org/10.1177/0363546516657827

Lee DC, Choi H, Oh JM, Lee J, Lee J, Lee HY, et al. Urban particulate matter regulates tight junction proteins by inducing oxidative stress via the akt signal pathway in human nasal epithelial cells. Toxicol Lett. 2020;333:33-41. https://doi.org/10.1016/j.toxlet.2020.07.017 PMid:32687961 DOI: https://doi.org/10.1016/j.toxlet.2020.07.017

Saheli M, Bayat M, Ganji R, Hendudari F, Kheirjou R, Pakzad M, et al. Human mesenchymal stem cells-conditioned medium improves diabetic wound healing mainly through modulating fibroblast behaviors. Arch Dermatol Res. 2020;312(5):325-36. https://doi.org/10.1007/s00403-019-02016-6 PMid:31786709 DOI: https://doi.org/10.1007/s00403-019-02016-6

Kucharzewski M, Rojczyk E, Wilemska-Kucharzewska K, Wilk R, Hudecki J, Los MJ. Novel trends in application of stem cells in skin wound healing. Eur J Pharmacol. 2019;843:307-15. https://doi.org/10.1016/j.ejphar.2018.12.012 PMid:30537490 DOI: https://doi.org/10.1016/j.ejphar.2018.12.012

Darlan DM, Munir D, Jusuf NK, Putra A, Ikhsan R, Alif I. In vitro regulation of IL-6 and TGF-ß by mesenchymal stem cells in systemic lupus erythematosus patients. Med Glas (Zenica). 2020;17(2):408-13. https://doi.org/10.17392/1186-20

Sungkar T, Putra A, Lindarto D, Sembiring RJ. Intravenous umbilical cord-derived mesenchymal stem cells transplantation regulates hyaluronic acid and interleukin-10 secretion producing low-grade liver fibrosis in experimental rat. Med Arch. 2020;74(3):177-82. https://doi.org/10.5455/medarh.2020.74.177-182 PMid:32801431 DOI: https://doi.org/10.5455/medarh.2020.74.177-182

Putra A, Ridwan FB, Putridewi AI, Kustiyah AR, Wirastuti K, Sadyah NA, et al. The role of TNF-α _induced MSCs on suppressive inflammation by increasing TGF-β _and IL-10. Open Access Maced J Med Sci. 2018;6(10):1779-83. https://doi.org/10.3889/oamjms.2018.404 PMid:30455748 DOI: https://doi.org/10.3889/oamjms.2018.404

You YJ, Wu PY, Liu YJ, Hou CW, Wu CS, Wen KC, et al. Sesamol inhibited ultraviolet radiation-induced hyperpigmentation and damage in C57BL/6 mouse skin. Antioxidants (Basel). 2019;8(7):207. https://doi.org/10.3390/antiox8070207 PMid:31284438 DOI: https://doi.org/10.3390/antiox8070207

Alam MB, Bajpai VK, Lee J, Zhao P, Byeon JH, Ra JS, et al. Inhibition of melanogenesis by jineol from Scolopendra subspinipes mutilans via MAP-kinase mediated MITF downregulation and the proteasomal degradation of tyrosinase. Sci Rep. 2017;7:45858. https://doi.org/10.1038/srep45858 PMid:28393917 DOI: https://doi.org/10.1038/srep45858

Pandel R, Poljšak B, Godic A, Dahmane R. Skin photoaging and the role of antioxidants in its prevention. ISRN Dermatol. 2013;2013:930164. https://doi.org/10.1155/2013/930164 PMid:24159392 DOI: https://doi.org/10.1155/2013/930164

Gupta A, Kaur CD, Jangdey M, Saraf S. Matrix metalloproteinase enzymes and their naturally derived inhibitors: Novel targets in photocarcinoma therapy. Ageing Res Rev. 2014;13(1):65-74. https://doi.org/10.1016/j.arr.2013.12.001 PMid:24355347 DOI: https://doi.org/10.1016/j.arr.2013.12.001

Lee SE, Park SH, Oh SW, Yoo JA, Kwon K, Park SJ, et al. Beauvericin inhibits melanogenesis by regulating cAMP/ PKA/CREB and LXR-α/p38 MAPK-mediated pathways. Sci Rep. 2018;8(1):14958. https://doi.org/10.1038/s41598-018-33352-8 PMid:30297846 DOI: https://doi.org/10.1038/s41598-018-33352-8

Rendon MI, Gaviria JI. Review of skin-lightening agents. Dermatol Surg. 2005;31(7 Pt 2):886-90; discussion 889. https://doi.org/10.1111/j.1524-4725.2005.31736 PMid:16029683 DOI: https://doi.org/10.1111/j.1524-4725.2005.31736

Zhao G, Liu F, Liu Z, Zuo K, Wang B, Zhang Y, et al. MSC-derived exosomes attenuate cell death through suppressing AIF nucleus translocation and enhance cutaneous wound healing. Stem Cell Res Ther. 2020;11(1):174. https://doi.org/10.1186/s13287-020-01616-8 PMid:32393338 DOI: https://doi.org/10.1186/s13287-020-01616-8

Al-Shaibani MB, Dickinson A, Nong-Wang X, Tulah AS, Lovat PE. Effect of conditioned media from mesenchymal stem cells (MSC-CM) on wound healing using a prototype of a fully humanised 3D skin model. Cytotherapy. 2017;19(5):e23-4. https://doi.org/10.1016/j.jcyt.2017.03.062 DOI: https://doi.org/10.1016/j.jcyt.2017.03.062

Jiang D, Jiang Y, Long S, Chen Z, Li Y, Mo G, et al. Spermidine at supraphysiological doses induces oxidative stress and granulosa cell apoptosis in mouse ovaries. Theriogenology. 2021;168:25-32. https://doi.org/10.1016/j.theriogenology.2021.03.026 PMid:33845261 DOI: https://doi.org/10.1016/j.theriogenology.2021.03.026

Hamra NF, Putra A, Tjipta A, Amalina ND, Nasihun T. Hypoxia Mesenchymal Stem Cells Accelerate Wound Closure Improvement by Controlling α-smooth muscle actin Expression in the Full-thickness Animal Model. Open Access Maced J Med Sci. 2021; 9(A):35-41. https://doi.org/10.3889/oamjms.2021.5537 DOI: https://doi.org/10.3889/oamjms.2021.5537

Jung KJ, Lee GW, Park CH, Lee TJ, Kim JY, Sung EG, et al. Mesenchymal stem cells decrease oxidative stress in the bowels of interleukin-10 knockout mice. Gut Liver. 2020;14(1):100-7. https://doi.org/10.5009/gnl18438 PMid:31158947 DOI: https://doi.org/10.5009/gnl18438

Lee S, Heo J, Ahn EK, Kim JH, Kim YH, Chang HK, et al. Conditioned secretome of adipose-derived stem cells improves dextran sulfate sodium-induced colitis in mice. World J Gastroenterol. 2021;27(23):3342-56. https://doi.org/10.3748/wjg.v27.i23.3342 PMid:34163116 DOI: https://doi.org/10.3748/wjg.v27.i23.3342

Astari L, Cahyono H, Widjajanto E. Correlation of interleukin-10, superoxide dismutase (SOD), and malondialdehyde (MDA) levels with HbA1c in pediatric Type 1 diabetes mellitus. J Trop Life Sci. 2017;7(3):286-92. https://doi.org/10.11594/jtls.07.03.15 DOI: https://doi.org/10.11594/jtls.07.03.15

Kim EH, Song HS, Yoo SH, Yoon M. Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis. Oncotarget. 2016;7(40):65125-36. https://doi.org/10.18632/oncotarget.11372 PMid:27556184 DOI: https://doi.org/10.18632/oncotarget.11372

Darlan DM, Munir D, Putra A, Alif I, Amalina ND, Karmila N, Jusuf IB. Revealing the decrease of indoleamine 2, 3-dioxygenase as a major constituent for B cells survival post-mesenchymal stem cells co-cultured with peripheral blood mononuclear cell (PBMC) of systemic lupus erythematosus (SLE) patients. Med Glas (Zenica). 2022;19(1). htpps://doi.org/10.17392/1414-21

Mazini L, Rochette L, Hamdan Y, Malka G. Skin immunomodulation during regeneration: Emerging new targets. J Pers Med. 2021;11(2):85. https://doi.org/10.3390/jpm11020085 PMid:33573342 DOI: https://doi.org/10.3390/jpm11020085

Lin PS, Chang HH, Yeh CY, Chang MC, Chan CP, Kuo HY, et al. Transforming growth factor beta 1 increases collagen content, and stimulates procollagen I and tissue inhibitor of metalloproteinase-1 production of dental pulp cells: Role of MEK/ERK and activin receptor-like kinase-5/smad signaling. J Formos Med Assoc. 2017;116(5):351-8. DOI: https://doi.org/10.1016/j.jfma.2016.07.014

Drawina P, Putra A, Nasihun T, Prajoko YW, Dirja BT, Amalina ND. Increased serial levels of platelet-derived growth factor using hypoxic mesenchymal stem cell-conditioned medium to promote closure acceleration in a full-thickness wound. Indonesian Journal of Biotechnology. 2022;27(1):36-42. https://doi.org/10.22146/ijbiotech.64021 DOI: https://doi.org/10.22146/ijbiotech.64021

Thepmalee C, Panya A, Junking M, Chieochansin T, Yenchitsomanus PT. Inhibition of IL-10 and TGF-β _receptors on dendritic cells enhances activation of effector T-cells to kill cholangiocarcinoma cells. Hum Vaccin Immunother. 2018;14(6):1423-31. https://doi.org/10.1080/21645515.2018.14 31598 PMid:29420117 DOI: https://doi.org/10.1080/21645515.2018.1431598

Hwang B, Song JH, Park SL, Kim JT, Kim WJ, Moon SK. Carnosine impedes PDGF-stimulated proliferation and migration of vascular smooth muscle cells in vitro and sprout outgrowth ex vivo. Nutrients. 2020;12(9):2697. https://doi.org/10.3390/nu12092697 PMid:32899420 DOI: https://doi.org/10.3390/nu12092697

Yao C, Lee DH, Oh JH, Kim MK, Kim KH, Park CH, et al. Poly(I :C) induces expressions of MMP-1, -2, and -3 through various signaling pathways including IRF3 in human skin fibroblasts. J Dermatol Sci. 2015;80(1):54-60. https://doi.org/10.1016/j.jdermsci.2015.06.017 PMid:26255711 DOI: https://doi.org/10.1016/j.jdermsci.2015.06.017

Mirastschijski U, Lupše B, Maedler K, Sarma B, Radtke A, Belge G, et al. Matrix metalloproteinase-3 is key effector of TNF-α-induced collagen degradation in skin. Int J Mol Sci. 2019;20(20):5234. https://doi.org/10.3390/ijms20205234 PMid:31652545 DOI: https://doi.org/10.3390/ijms20205234




How to Cite

Zukhiroh Z, Putra A, Chodidjah C, Sumarawati T, Subchan P, Trisnadi S, Hidayah N, Amalina ND. Effect of Secretome-Hypoxia Mesenchymal Stem Cells on Regulating SOD and MMP-1 mRNA Expressions in Skin Hyperpigmentation Rats. Open Access Maced J Med Sci [Internet]. 2022 Dec. 15 [cited 2023 Mar. 28];10(A):1-7. Available from: https://oamjms.eu/index.php/mjms/article/view/10348





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