Topical Instillation of Resveratrol Preconditioned Wharton’s Jelly Mesenchymal Stem Cell Secretome Preserves Ocular Surface in Experimental Model of Severe Dry Eye Disease

Diandra Astaridewi; Evelyn Komaratih; Yuyun Rindiastuti; Yohanes Widodo Wirohadidjojo; Djoko Legowo; Ni Made Inten Lestari; Diandra Astari Dewi; I. Made Satya; Fedik A. Rantam; Cita R. S. Prakoeswa

doi:10.3889/oamjms.2020.5305

Authors

Diandra Astaridewi Department of Ophthalmology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
Evelyn Komaratih Department of Ophthalmology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
Yuyun Rindiastuti Department of Ophthalmology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
Yohanes Widodo Wirohadidjojo Department of Dermatovenerology, Faculty of Medicine, Universitas Gadjah Mada, Dr. Sardjito General Academic Hospital, Radioputro Building, Yogyakarta, Indonesia
Djoko Legowo Department of Pathology Anatomy, Faculty of Veterinary Medicine, Universitas Airlangga, Kampus C Mulyorejo, Surabaya, Indonesia
Ni Made Inten Lestari Department of Ophthalmology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
Diandra Astari Dewi Department of Ophthalmology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
I. Made Satya Department of Ophthalmology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
Fedik A. Rantam Stem Cell Research and Development Center, Universitas Airlangga, Tropical Disease Center Building, Kampus C Mulyorejo, Surabaya, Indonesia
Cita R. S. Prakoeswa Department of Dermatovenerology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2020.5305

Keywords:

Mesenchymal stem cell, Resveratrol, Secretome, Dry eye disease, Ocular surface

Abstract

BACKGROUND: Secretome derived from Wharton’s jelly mesenchymal stem cells (WJ-MSC) has a beneficial effect for ocular surface regeneration; however, the high amount of vascular endothelial growth factor (VEGF) remains a challenge for its application.

AIM: The aim of the study was to investigate the effect of resveratrol (RV) (VEGF reducing agent) preconditioned WJ-MSC secretome in Concanavalin A-induced severe dry eye model.

METHODS: Pre- and post-experimental study composed of topical instillation of WJ-MSC secretome group, balanced salt solution control group, and normal control group. Tear production, tear break-up time (TBUT), corneal fluorescein dye staining, VEGF level in aqueous tear, goblet cell density, and inflammatory cells in the ocular surface were analyzed.

RESULTS: Topical instillation of RV preconditioned WJ-MSC secretome successfully improved tear film production (p = 0.008) and TBUT (p = 0.008), promoted goblet cell restoration (p = 0.023) and reduced corneal fluorescein staining (p = 0.003), while inhibited infiltration of inflammatory cells (p = 0.01) and secretion of VEGF in aqueous tear (p = 0.003).

CONCLUSION: Topical instillation of RV preconditioned WJ-MSC secretome has great potential as cell-free based therapy to preserve ocular surface in an experimental model of severe Dry eye disease.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Villatoro AJ, Fernández V, Claros S, Alcoholado C, Cifuentes M, Merayo-Lloves J, et al. Regenerative therapies in dry eye disease: From growth factors to cell therapy. Int J Mol Sci. 2017;18(11):2264. https://doi.org/10.3390/ijms18112264 PMid:29143779

Villatoro AJ, Fernández V, Claros S, Rico-Llanos GA, Becerra J, Andrades JA. Use of adipose-derived mesenchymal stem cells in keratoconjunctivitis sicca in a canine model. Biomed Res Int. 2015;2015:527926. https://doi.org/10.1155/2015/527926 PMid:25802852

Baradaran-Rafii A, Asl NS, Ebrahimi M, Jabbehdari S, Bamdad S, Roshandel D, et al. The role of amniotic membrane extract eye drop (AMEED) in in vivo cultivation of limbal stem cells. Ocul Surf. 2017;16(1):146-53. https://doi.org/10.1016/j.jtos.2017.11.001 PMid:29104070

Dudok DV, Nagdee I, Cheung K, Liu H, Vedovelli L, Ghinelli E, et al. Effects of amniotic membrane extract on primary human corneal epithelial and limbal cells. Clin Exp Ophthalmol. 2015;43(5):443-8. https://doi.org/10.1111/ceo.12480 PMid:25495256

Seong H, Ryu J, Jeong JY, Chung IY, Han YS, Hwang SH, et al. Resveratrol suppresses vascular endothelial growth factor secretion via inhibition of CXC-chemokine receptor 4 expression in ARPE-19 cells. Mol Med Rep. 2015;12(1):1479-84. https://doi.org/10.3892/mmr.2015.3518 PMid:25815440

Safaeinejad Z, Kazeminasab F, Kiani-Esfahani A, Ghaedi K, Nasr-Esfahani MH. Multi-effects of resveratrol on stem cell characteristics: Effective dose, time, cell culture conditions and cell type-specific responses of stem cells to resveratrol. Eur J Med Chem. 2018;155:651-7. https://doi.org/10.1016/j.ejmech.2018.06.037 PMid:29935438

Song JK, Lee K, Park HY, Hyon JY, Oh SW, Bae WK, et al. Efficacy of carboxymethylcellulose and hyaluronate in dry eye disease: A systematic review and meta-analysis. Korean J Fam Med. 2017;38(1):2-7. https://doi.org/10.4082/kjfm.2017.38.1.2 PMid:28197326

Aluri HS, Samizadeh M, Edman MC, Hawley DR, Armaos HL, Janga SR, et al. Delivery of bone marrow-derived mesenchymal stem cells improves tear production in a mouse model of Sjögren’s syndrome. Stem Cells Int. 2017;2017:3134543. https://doi.org/10.1155/2017/3134543 PMid:28348600

Beyazyıldız E, Pınarlı FA, Beyazyıldız O, Hekimoğlu ER, Acar U, Demir MN. Efficacy of topical mesenchymal stem cell therapy in the treatment of experimental dry eye syndrome model. Stem Cells Int. 2014;2014:250230. https://doi.org/10.1155/2014/250230 PMid:25136370

Komaratih E, Rindiastuti Y, Wirohadidjojo YW, Rantam FA, Dinaryati A, Lestari NM, et al. The resveratrol increase of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) levels in wharton’s jelly mesenchymal stem cells (WJ-MSCs) secretome: Toward cell free therapy in dry eye disease (DED). Biochem Cell Arch. 2019;19(2):1-7. https://doi.org/10.1080/21691401.2020.1817057

Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016;7(1):125. https://doi.org/10.1186/s13287-016-0363-7 PMid:27581859

Sánchez-Abarca LI, Hernández-Galilea E, Lorenzo R, Herrero C, Velasco A, Carrancio S, et al. Human bone marrow stromal cells differentiate into corneal tissue and prevent ocular graft-versus-host disease in mice. Cell Transplant. 2015;24(12):2423-33. https://doi.org/10.3727/096368915x687480 PMid:25695936

Stevenson W, Chauhan SK, Dana R. Dry eye disease: An immune-mediated ocular surface disorder. Arch Ophthalmol. 2012;130(1):90-100. https://doi.org/10.1001/archophthalmol.2011.364 PMid:22232476

Bron AJ, De Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438-510. https://doi.org/10.1016/j.jtos.2019.08.007 PMid:28736340

Lee MJ, Ko AY, Ko JH, Lee HJ, Kim MK, Wee WR, et al. Mesenchymal stem/stromal cells protect the ocular surface by suppressing inflammation in an experimental dry eye. Mol Ther. 2015;23(1):139-46. https://doi.org/10.1038/mt.2014.159 PMid:25152016

Bittencourt MK, Barros MA, Martins JF, Vasconcellos JP, Morais BP, Pompeia C, et al. Allogeneic mesenchymal stem cell transplantation in dogs with keratoconjunctivitis sicca. Cell Med. 2016;8(3):63-77. https://doi.org/10.3727/215517916x693366 PMid:28003932

Glenn JD, Whartenby KA. Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy. World J Stem Cells. 2014;6(5):526-39. https://doi.org/10.4252/wjsc.v6.i5.526 PMid:25426250

Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Open Access Maced J Med Sci. 2020 Oct 30; 8(B):1116-1123. 1123 Kao WW. Extrinsic and intrinsic mechanisms by which mesenchymal stem cells suppress the immune system. Ocul Surf. 2016;14(2):121-34. https://doi.org/10.1016/j.jtos.2015.11.004 PMid:26804815

Su W, Wan Q, Huang J, Han L, Chen X, Chen G, et al. Culture medium from TNF-α-stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms. J Allergy Clin Immunol. 2015;136(2):423-32. https://doi.org/10.1016/j.jaci.2014.12.1926 PMid:25652765

Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II epidemiology report. Ocul Surf. 2017;15(3):334-65. https://doi.org/10.1016/j.jtos.2017.05.003 PMid:28736337

Wen L, Zhu M, Madigan MC, King NJ, Billson FA, McClellan K, et al. Immunomodulatory effects of bone marrow-derived mesenchymal stem cells on pro-inflammatory cytokine-stimulated human corneal epithelial cells. PLoS One. 2014;9(7):e101841. https://doi.org/10.1371/journal.pone.0101841 PMid:25003339

Murri MS, Moshirfar M, Birdsong OC, Ronquillo Y, Ding Y, Hoopes PC. Amniotic membrane extract and eye drops: A review of literature and clinical application. Clin Ophthalmol. 2018;12:1105-23. https://doi.org/10.2147/opth.s165553 PMid:29950805

Magaña-Guerrero FS, Domínguez-López A, Martínez- Aboytes P, Buentello-Volante B, Garfias Y. Human amniotic membrane mesenchymal stem cells inhibit neutrophil extracellular traps through TSG-6. Sci Rep. 2017;7(1):12426. https://doi.org/10.1038/s41598-017-10962-2 PMid:28963485

Javorkova E, Trosan P, Zajicova A, Krulova M, Hajkova M, Holan V. Modulation of the early inflammatory microenvironment in the alkali-burned eye by systemically administered interferon- γ-treated mesenchymal stromal cells. Stem Cells Dev. 2014;23(20):2490-500. https://doi.org/10.1089/scd.2013.0568 PMid:24849741

Bermudez MA, Sendon-Lago J, Eiro N, Treviño M, Gonzalez F, Yebra-Pimentel E, et al. Corneal epithelial wound healing and bactericidal effect of conditioned medium from human uterine cervical stem cells. Invest Ophthalmol Vis Sci. 2015;56(2):983- 92. https://doi.org/10.1167/iovs.14-15859 PMid:25613942

Ljubimov AV, Saghizadeh M. Progress in corneal wound healing. Prog Retin Eye Res. 2015;49:17-45. https://doi.org/10.1016/j.preteyeres.2015.07.002 PMid:26197361

Oh JY, Ko JH, Kim MK, Wee WR. Effects of mesenchymal stem/ stromal cells on cultures of corneal epithelial progenitor cells with ethanol injury. Invest Ophthalmol Vis Sci. 2014;55(11):7628-35. https://doi.org/10.1167/iovs.14-15424 PMid:25370509

Sendon-Lago J, Seoane S, Martinez-Ordonez A, Eiro N, Saa J, Vizoso FJ, et al. Corneal regeneration by conditioned medium of human uterine cervical stem cells is mediated by TIMP-1 and TIMP-2. Exp Eye Res. 2019;180:110-21. https://doi.org/10.1016/j.exer.2018.12.004 PMid:30557571

Anderson JD, Johansson HJ, Graham, CS, Vesterlund M, Pham MT, Bramlett CS, et al. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells. 2016;34(3):601-13. https://doi.org/10.1002/stem.2298 PMid:26782178

Navas A, Magana-Guerrero FS, Dominguez-Lopez A, Chavez-Garcia C, Partido G, Graue-Hernandez EO, et al. Anti-inflammatory and anti-fibrotic effects of human amniotic membrane mesenchymal stem cells and their potential in corneal repair. Stem Cells Transl Med. 2018;7(12):906-17. https://doi.org/10.1002/sctm.18-0042 PMid:30260581