Evaluation of the retina and optic nerve after the use of stem cells for neurodegenerative disorders in an animal model
Romana García-Gil, Anselmo Feliciano-Sanchez, Laura Cubas-Nuñez, Jessica Castillo-Villalba, Jorge Fuentes-Maestre, Mariana Fil, Jose M. García-Verdugo, Sara Gil-Perotin
Citation Information :
García-Gil R, Feliciano-Sanchez A, Cubas-Nuñez L, Castillo-Villalba J, Fuentes-Maestre J, Fil M, García-Verdugo JM, Gil-Perotin S. Evaluation of the retina and optic nerve after the use of stem cells for neurodegenerative disorders in an animal model. 2019; 93 (6E):264-273.
Objective: To study the neuroprotective and neuroregenerative response of adult mesenchymal cells (aMSCs) on retinal ganglion cells (RGC) and optic nerve (ON) in an animal model of multiple sclerosis (MS) like experimental autoimmune encephalitis (EAE). Methods: We studied the changes that occurred in the retina and ON, analyzing the effect of an intravenous injection of aMSCs. Three groups were studied: healthy (control), sick (EAE) and sick treated with aMSCs (EAE-MSC). The animals were monitored using motor disability scales. The retinas and ONs were studied with optical microscopy, immunofluorescence and electron microscopy. Results: The results showed that after administration of intravenous aMSCs there was a lower loss of RGC, the average of RGC in the EAE group was of 0.0891 ìm compared to 0.166 ìm in the EAE-MSC group, with a statistically significant p value (p = 0.01). There was a reduction in the inflammatory cell response of the ON (7.99 cells/ìm2 vs. 3.69 cells/ìm2, p < 0.0001), a decrease of myelin loss (overall axonal damage was of 54% compared to 88%) and less axonal destruction (0.16745 axons/ìm2 vs. 0.3598 axons/ìm2 (p = 0.0251). Conclusions: In this study, we found that after the administration of aMSCs there was a lower loss of RGC, a decrease of myelin loss and a lower degree of inflammation in the ON. However, it would be advisable to expand the methodology to ensure an immunosuppressive and neuroprotective effect in this model.
Noseworthy JH. Progress in determining the causes and treatment of multiple sclerosis. Nature. 2000;399:A40–7.
Dolati S, Babaloo Z, Jadidi-Niaragh F, Ayromlou H, Sadreddini S, Youse M. Multiple sclerosis: Therapeutic applications of advancing drug delivery systems. Biomed Pharmacother. 2017;86:343-53.
Dominici M, Le Blanc K, Mueller I, Marini FC, Krause DS, Deans RJ, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7.
Galderisi U, Giordano A. The Gap Between the Physiological and Therapeutic Roles of Mesenchymal Stem Cells. Med Res Rev. 2014;34(5):1100-26.
De Miguel MP, Fuentes-Julián S, Blazquez-Martínez A, Pascual CY, Aller MA, Arias J, et al. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med. 2012;12(5):574-91.
Yagi H, Soto-gutierrez A, Parekkadan B, Kitagawa Y, Tompkins G, Kobayashi N, et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. October. 2010;19(6):667-79.
Shindler KS, Guan Y, Ventura E, Benett J, Rostami A. Retinal Ganglion Cell Loss Induced By Acute Optic Neuritis in Relapsing Model of Multiple Sclerosis. Mult Scleros. 2006;12(5):526-32.
Horstmann L, Schmid H, Heinen AP, Kurschus FC, Dick HB, Joachim SC. Inflammatory demyelination induces glia alterations and ganglion cell loss in the retina of an experimental autoimmune encephalomyelitis model. J Neuroinflammation. 2013;10:1-12.
Feliciano-Sanchez A, García-Gil R, Cubas-Nuñez L, Castillo-Villalba J, Fuentes-Maestre J, Fil M, et al. Development and optimisation of an animal model for the study of ganglion cells in degenerative diseases of the retina and optic nerve. Arch la Soc Española Oftalmol. 2019;94(6):263-72.
Pierini M, Dozza B, Lucarelli E, Tazzari PL, Ricci F, Remondini D, et al. Efficient isolation and enrichment of mesenchymal stem cells from bone marrow. Cytotherapy. 2012;14(6):686-93.
Garcia-Contreras M, Vera-Donoso CD, Hernandez-Andreu JM, Garcia-Verdugo JM, Oltra E. Therapeutic potential of human Adipose-Derived Stem Cells (ADSCs) from cancer patients: A pilot study. PLoS One. 2014;9(11):e113288.
Chomiak T, Hu B. What is the optimal value of the g-ratio for myelinated fibers in the rat CNS? A theoretical approach. PLoS One. 2009;4(11):e7754.
Selles-Navarro I, Villegas-Perez MP, Salvador-Silva M, Ruiz-Gomez JM, Vidal-Sanz M. Retinal ganglion cell death after different transient periods of pressure-induced ischemia and survival intervals: A quantitative in vivo study. Investig Ophthalmol Vis Sci. 1996;37(10):2002-14.
Borsello T, Mottier V, Castagne V, Clarke PGH. Ultrastructure of retinal ganglion cell death after axotomy in chick embryos. J Comp Neurol. 2002;453(4):361-71.
Galindo-Romero C, Aviles-Trigueros M, Jimenez-Lopez M, Valiente-Soriano FJ, Salinas-Navarro M, Nadal-Nicolas F, et al. Axotomy-induced retinal ganglion cell death in adult mice: Quantitative and topographic time course analyses. Exp Eye Res. 2011;92(5):377-87.
Guan Y, Shindler KS, Tabuena P, Rostami AM. Retinal ganglion cell damage induced by spontaneous autoimmune optic neuritis in MOG-specific TCR transgenic mice. J Neuroimmunol. 2006;178(1-2):40-8.
Hu P, Pollard J, Hunt N, Chan-Ling T. Microvascular and cellular responses in the retina of rats with acute experimental allergic encephalomyelitis (EAE). Brain Pathol. 1998;8(3):487-98.
Daldrup-Link HE, Rudelius M, Metz S, Piontek G, Pichler B, Settles M, et al. Cell tracking with gadophrin-2: a bifunctional contrast agent for MR imaging, optical imaging, and fluorescence microscopy. Eur J Nucl Med Mol Imaging. 2004;31(9):1312-21.
Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001;169(1):12-20.
Rochefort GY, Vaudin P, Bonnet N, Pages J-C, Domenech J, Charbord P, et al. Influence of hypoxia on the domiciliation of mesenchymal stem cells after infusion into rats: possibilities of targeting pulmonary artery remodeling via cells therapies? Respir Res. 2005;6:125.
Kang WJ, Kang H-J, Kim H-S, Chung J-K, Lee MC, Lee DS. Tissue distribution of 18F-FDG-labeled peripheral hematopoietic stem cells after intracoronary administration in patients with myocardial infarction. J Nucl Med. 2006;47(8):1295-301.
Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-ƑÁ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. 2007;149(2):353-63.
Mazhari R, Hare JM. Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche. Nat Clin Pract Cardiovasc Med. 2007;4 Suppl 1:S21-6.
Ankrum JA, Faii Ong J, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252-60.
Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014;15(3):4142-57.
Fischer MD, Huber G, Beck SC, Tanimoto N, Muehlfriedel R, Fahl E, et al. Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography. PLoS One. 2009;4(10):e7507.
