The aim of this study was to investigate the effects of systemically administered bone-marrow-derived mesenchymal stromal cells (MSCs) on the early acute phase of inflammation in the alkali-burned eye. Mice with damaged eyes were either untreated or treated 24 h after the injury with an intravenous administration of fluorescent-dye-labeled MSCs that were unstimulated or pretreated with interleukin-1α (IL-1α), transforming growth factor-β (TGF-β), or interferon-γ (IFN-γ). Analysis of cell suspensions prepared from the eyes of treated mice on day 3 after the alkali burn revealed that MSCs specifically migrated to the damaged eye and that the number of labeled MSCs was more than 30-times higher in damaged eyes compared with control eyes. The study of the composition of the leukocyte populations within the damaged eyes showed that all types of tested MSCs slightly decreased the number of infiltrating lymphoid and myeloid cells, but only MSCs pretreated with IFN-γ significantly decreased the percentage of eye-infiltrating cells with a more profound effect on myeloid cells. Determining cytokine and NO production in the damaged eyes confirmed that the most effective immunomodulation was achieved with MSCs pretreated with IFN-γ, which significantly decreased the levels of the proinflammatory molecules IL-1α, IL-6, and NO. Taken together, the results show that systemically administered MSCs specifically migrate to the damaged eye and that IFN-γ-pretreated MSCs are superior in inhibiting the acute phase of inflammation, decreasing leukocyte infiltration, and attenuating the early inflammatory environment.

Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague Czech Republic

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O'Brien TP, Li Q, Ashraf MF, Matteson DM, Stark WJ. and Chan CC. (1998). Inflammatory response in the early stages of wound healing after excimer laser keratectomy. Arch Ophthalmol 116:1470–1474 PubMed

Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R. and De Luca M. (1997). Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 349:990–993 PubMed

Du Y, Chen J, Funderburgh JL, Zhu X. and Li L. (2003). Functional reconstruction of rabbit corneal epithelium by human limbal cells cultured on amniotic membrane. Mol Vis 9:635–643 PubMed PMC

Basu S, Ali H. and Sangwan VS. (2012). Clinical outcomes of repeat autologous cultivated limbal epithelial transplantation for ocular surface burns. Am J Ophthalmol 153:643–650 PubMed

Marchini G, Pedrotti E, Pedrotti M, Barbaro V, Di Iorio E, Ferrari S, Bertolin M, Ferrari B, Passilongo M, Fasolo A. and Ponzin D. (2012). Long-term effectiveness of autologous cultured limbal stem cell grafts in patients with limbal stem cell deficiency due to chemical burns. Clin Exp Ophthalmol 40:255–267 PubMed

Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S. and Marshak DR. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147 PubMed

Gu S, Xing C, Han J, Tso MO. and Hong J. (2009). Differentiation of rabbit bone marrow mesenchymal stem cells into corneal epithelial cells in vivo and ex vivo. Mol Vis 15:99–107 PubMed PMC

PăunescuV , Deak E, Herman D, Siska IR, Tănasie G, Bunu C, Anghel S, Tatu CA, Oprea TI, et al. (2007). In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J Cell Mol Med 11:502–508 PubMed PMC

Nieto-Miguel T, Galindo S, Reinoso R, Corell A, Martino M, Pérez-Simón JA. and Calonge M. (2013). In vitro simulation of corneal epithelium microenvironment induces a corneal epithelial-like cell phenotype from human adipose tissue mesenchymal stem cells. Curr Eye Res 38:933–944 PubMed

Aggarwal S. and Pittenger MF. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822 PubMed

Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, et al. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48 PubMed

Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, et al. (2008). Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol 181:3933–3946 PubMed

Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, et al. (2005). Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761 PubMed

Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M. and Ringdén O. (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441 PubMed

Jiang TS, Cai L, Ji WY, Hui YN, Wang YS, Hu D. and Zhu J. (2010). Reconstruction of the corneal epithelium with induced marrow mesenchymal stem cells in rats. Mol Vis 16:1304–1316 PubMed PMC

Oh JY, Kim MK, Shin MS, Lee HJ, Ko JH, Wee WR. and Lee JH. (2008). The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells 26:1047–1055 PubMed

Ma Y, Xu Y, Xiao Z, Yang W, Zhang C, Song E, Du Y. and Li L. (2006). Reconstruction of chemically burned rat corneal surface by bone marrow-derived human mesenchymal stem cells. Stem Cells 24:315–321 PubMed

Yao L, Li ZR, Su WR, Li YP, Lin ML, Zhang WX, Liu Y, Wan Q. and Liang D. (2012). Role of mesenchymal stem cells on cornea wound healing induced by acute alkali burn. PLoS One 7:e30842. PubMed PMC

Roddy GW, Oh JY, Lee RH, Bartosh TJ, Ylostalo J, Coble K, Rosa RH., Jr. and Prockop DJ. (2011). Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-α stimulated gene/protein 6. Stem Cells 29:1572–1579 PubMed

Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M. and Lagneaux L. (2012). Immune-related antigens, surface molecules and regulatory factors in human-derived mesenchymal stromal cells: the expression and impact of inflammatory priming. Stem Cell Rev 8:1188–1198 PubMed

Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC. and Shi Y. (2008). Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2:141–150 PubMed

English K, Barry FP, Field-Corbett CP. and Mahon BP. (2007). IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 110:91–100 PubMed

Svobodova E, Krulova M, Zajicova A, Pokorna K, Prochazkova J, Trosan P. and Holan V. (2012). The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. Stem Cells Dev 21:901–910 PubMed PMC

Trosan P, Svobodova E, Chudickova M, Krulova M, Zajicova A. and Holan V. (2012). The key role of insulin-like growth factor I in limbal stem cell differentiation and the corneal wound-healing process. Stem Cells Dev 21:3341–3350 PubMed PMC

Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS. and Tannenbaum SR. (1982). Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138 PubMed

Hemeda H, Jakob M, Ludwig AK, Giebel B, Lang S. and Brandau S. (2010). Interferon-gamma and tumor necrosis factor-alpha differentially affect cytokine expression and migration properties of mesenchymal stem cells. Stem Cells Dev 19:693–706 PubMed

Duijvestein M, Wildenberg ME, Welling MM, Hennink S, Molendijk I, van Zuylen VL, Bosse T, Vos AC, de Jonge-Muller ES, et al. (2011). Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells 29:1549–1558 PubMed

Lan Y, Kodati S, Lee HS, Omoto M, Jin Y. and Chauhan SK. (2012). Kinetics and function of mesenchymal stem cells in corneal injury. Invest Ophthalmol Vis Sci 53:3638–3644 PubMed

Ye J, Yao K. and Kim JC. (2006). Mesenchymal stem cell transplantation in a rabbit corneal alkali burn model: engraftment and involvement in wound healing. Eye (Lond) 20:482–490 PubMed

Sotozono C, He J, Matsumoto Y, Kita M, Imanishi J. and Kinoshita S. (1997). Cytokine expression in the alkali-burned cornea. Curr Eye Res 16:670–676 PubMed

Ryan JM, Barry F, Murphy JM. and Mahon BP. (2007). Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149:353–363 PubMed PMC

Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, et al. (2006). Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24:386–398 PubMed

Holán V, Krulová M, Zajícová A. and Pindjáková J. (2002). Nitric oxide as a regulatory and effector molecule in the immune system. Mol Immunol 38:989–995 PubMed

Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, et al. (2002). Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297:1867–1870 PubMed

Meisel R, Zibert A, Laryea M, Göbel U, Däubener W. and Dilloo D. (2004). Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103:4619–4621 PubMed

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