Potential Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-evs) as the Latest Therapy in Retinal Ischemic Medicine

Sisca Sisca, Nurul Azizah, M.Salas Al Aldi


Background: Retinal ischemia (IR) is still the biggest cause of blindness in the world. Several factors contribute to the pathogenesis of Retinal Ischemia. However, oxidative stress and inflammatory processes are the main factors. Various forms of therapy have been applied in clinical care of Retinal ischemia, but none have been optimal for repairing the cells damage and able to avoid immunological and oncogenic reactions. MSC-EVs have opened a new perspective for the treatment of Retinal Ischemia. MSC is a multipotent cell with paracrine characteristic and mediated by extracellular vesicles (EVs) which is derivative of MSC that can be used as a biomimetic agent to help nerve protection and tissue regeneration. In addition, MSC-EVs have a lower tendency to trigger immune responses and the inability to directly form tumors. Therefore, MSC EVs can prove to be an ideal source for the latest therapies in dealing with the problem of retinal ischemia.

Method: This Literature Riview is compiled by using a literature study with collecting valid journals, particular inclusion and exclusion criteria

Results: On testing its effectiveness, three indicators were used, that is the protective effect of MSC-EVs on retinal cells, the effects of post-ischemic in vivo administration of MSC-EVs, and the distribution of MSC-EVs in humour vitreous and long-term protective effects estimates. Significantly shows a protective effect, decreases inflammatory factors and apoptosis of

retinal cells.

Conclusion: Based on the results of testing in vitro and in vivo MSC-EVs are endocytosis by retinal cells that provide neuroprotective effects before and after treatment, and this effect can be developed into long-term therapy. Therefore, using MSC-EVs can be a promising therapy in the treatment of retinal ischemia.

Keywords              : EVs, Iskemia Retina , MSC, Sel Retina R28.

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Rivera JC, Dabouz R, Noueihed B, Omri S, Tahiri H, Chemtob S. Review Article Ischemic Retinopathies : Oxidative Stress and Inflammation. 2017;2017.

Mathew B, Ravindran S, Liu X, Torres L, Chennakesavalu M, Huang C, et al. Biomaterials Mesenchymal stem cell-derived extracellular vesicles and retinal ischemia- reperfusion. Biomaterials [Internet].Elsevier;2019;197(June2018):146–60. Available from: https://doi.org/10.1016/j.biomaterials.2019.01.016

P. Sapieha, D. Hamel, Z. Shao et al., “Proliferative retinopathies: angiogenesis that blinds,” The International Journal of Biochemistry & Cell Biology, vol. 42, no. 1, pp. 5–12, 2010.

Y. Wu, L. Tang, and B. Chen, “Oxidative stress: implications for the development of diabetic retinopathy and antioxidant therapeutic perspectives,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 752387, 12 pages, 2014.

P. X. Shaw, T. Stiles, C. Douglas et al., “Oxidative stress, innate immunity, and age-related macular degeneration,” AIMS Molecular Science, vol. 3, no. 2, pp. 196–221, 2016.

F. Semeraro, A. Cancarini, R. dell'Omo, S. Rezzola, M. R. Romano, and C. Costagliola, “Diabetic retinopathy: vascular and inflammatory disease,” Journal of Diabetes Research, vol. 2015, Article ID 582060, 16 pages, 2015.

S. G. Jarrett and M. E. Boulton, “Consequences of oxidative stress in age-related macular degeneration,” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 399–417, 2012

Minhas G, Morishita R, Anand A. Preclinical models to investigate retinal ischemia : advances and drawbacks. 2012;3(May):1–7.

B. Yu, X. Zhang, X. Li, Exosomes derived from mesenchymal stem cells, Int. J. Mol. Sci. 15 (3) (2014) 4142–4157.

H.J. Kim, J.S. Park, Usage of human mesenchymal stem cells in cell-based therapy: advantages and disadvantages, Dev. Reprod. 21 (1) (2017) 1–10.

11. M. Gnecchi, Z. Zhang, A. Ni, V.J. Dzau, Paracrine mechanisms in adult stem cell

Mathew, B.; Ravindran, S.; Liu, X.; Torres, L.; et al. Mesenchymal stem-cell derived extracellular vesicles and retinal ischemia-reperfusion. [Internet]. Elsevier; 2019;197(June 2018):146–60. Available from: https://doi.org/10.1016/j.biomaterials.2019.01.016

Barry, FP and Murphy, JM (2004). Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol 36: 568–584

Crapnell, K, Blaesius, R, Hastings, A, Lennon, DP, Caplan, AI and Bruder, SP (2013). Growth, differentiation capacity, and function of mesenchymal stem cells expandedin serum-free medium developed via combinatorial screening. Exp Cell Res 319: 1409–1418

http://www.clinicaltrials. gov; accessed Mei 2019

Aurich, H.; Sgodda, M.; Kaltwasser, P.; Vetter, M.; Weise, A.; Liehr, T.; Brulport, M.; Hengstler, J.G.; Dollinger, M.M.; Fleig, W.E.; et al. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut 2009, 4, 570–581.

Matsuse, D.; Kitada, M.; Kohama, M.; Nishikawa, K.; Makinoshima, H.; Wakao, S.; Fujiyoshi, Y.; Heike, T.; Nakahata, T.; Akutsu, H.; et al. Human umbilical cord-derived mesenchymal stromal cells differentiate into functional Schwann cells that sustain peripheral nerve regeneration. J. Neuropathol. Exp. Neurol. 2010, 9, 973–985.

Reinshagen, H.; Auw-Haedrich, C.; Sorg, R.V.; Boehringer, D.; Eberwein, P.; Schwartzkopff, J.; Sundmacher, R.; Reinhard, T. Corneal surface reconstruction using adult mesenchymal stem cells in experimental limbal stem cell deficiency in rabbits. Acta Ophthalmol. 2011, 8, 741–748.

Johnson, T.V.; Bull, N.D.; Hunt, D.P.; Marina, N.; Tomarev, S.I.; Martin, K.R. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Investig. Ophthalmol. Vis. Sci. 2010, 4, 2051–2059.

Raposo, G.; Nijman, H.W.; Stoorvogel, W.; Liejendekker, R.; Harding, C.V.; Melief, C.J.; Geuze, H.J. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 1996, 183, 1161–1172. [CrossRef] [PubMed]

Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–659.

Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–579.

Kahlert C, et al. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem. 2014;289(7):3869–3875.

Ratajczak J, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20(5):847–856.

Maas SLN, Breakefield XO, Weaver AM, Hospital MG. Extracellular vesicles: unique intercellular delivery vehicles. 2018;27(3):172–88.

J.M. Pitt, G. Kroemer, L. Zitvogel, Extracellular vesicles: masters of intercellular communication and potential clinical interventions, J. Clin. Investig. 126 (4) (2016) 1139–1143.

Lai, RC, Yeo, RW, Tan, KH and Lim, SK (2013). Exosomes for drug delivery—a novel application for the mesenchymal stem cell. Biotechnol Adv 31: 543–551 28. L.A. Mulcahy, R.C. Pink, D.R. Carter, Routes and mechanisms of extracellular ve- sicle uptake, J. Extracell. Vesicles 3 (2014)

M.B. Goncalves, T. Malmqvist, E. Clarke, C.J. Hubens, J. Grist, C. Hobbs, D. Trigo, M. Risling, M. Angeria, P. Damberg, T.P. Carlstedt, J.P. Corcoran, Neuronal RARbeta signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord re- generation, J. Neurosci. : Official J. Soc. Neurosci. 35 (47) (2015) 15731–15745.

B. Zhang, Y. Yin, R.C. Lai, S.K. Lim, Immunotherapeutic potential of extracellular vesicles, Front. Immunol. 5 (2014) 518.

T.R. Doeppner, J. Herz, A. Gorgens, J. Schlechter, A.K. Ludwig, S. Radtke, K. de Miroschedji, P.A. Horn, B. Giebel, D.M. Hermann, Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression, Stem Cell. Trans. Med. 4 (10) (2015) 1131–1143.

M. Khan, E. Nickoloff, T. Abramova, J. Johnson, S.K. Verma, P. Krishnamurthy, A.R. Mackie, E. Vaughan, V.N. Garikipati, C. Benedict, V. Ramirez, E. Lambers, A. Ito, E. Gao, S. Misener, T. Luongo, J. Elrod, G. Qin, S.R. Houser, W.J. Koch, R. Kishore, Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction, Circ. Res. 117 (1) (2015) 52–64.

V. Zappulli, K.P. Friis, Z. Fitzpatrick, C.A. Maguire, X.O. Breakefield, Extracellular vesicles and intercellular communication within the nervous system, J. Clin. Investig. 126 (4) (2016) 1198–1207.

L.A. Beninson, M. Fleshner, Exosomes: an emerging factor in stress-induced im- munomodulation, Semin. Immunol. 26 (5) (2014) 394–401

Jarmalavičiūtė A, Pivoriūnas A. Exosomes as a potential novel therapeutic tools against neurodegenerative diseases. Pharmacol Res. 2016 Feb 6. Epub ahead of print. doi: 10.1016/j.phrs.2016.02.002

Lener T, et al. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles. 2015; 4:30087.doi: 10.3402/jev.v4.30087 [PubMed: 26725829]

T.V. Johnson, N.D. Bull, K.R. Martin, Identification of barriers to retinal engraftment of transplanted stem cells, Investig. Ophthalmol. Visual Sci. 51 (2)(2010) 960–970.

Y. Yao, J. Huang, Y. Geng, H. Qian, F. Wang, X. Liu, M. Shang, S. Nie, N. Liu, X. Du, J. Dong, C. Ma, Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts, PLoS One 10 (6) (2015) e0129164

R. Narayanan, C.C. Huang, S. Ravindran, Hijacking the cellular mail: exosome mediated differentiation of mesenchymal stem cells, Stem Cell. Int. 2016 (2016) 3808674.

M.B. Goncalves, T. Malmqvist, E. Clarke, C.J. Hubens, J. Grist, C. Hobbs, D. Trigo, M. Risling, M. Angeria, P. Damberg, T.P. Carlstedt, J.P. Corcoran, Neuronal RARbeta signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration, J. Neurosci. : Official J. Soc. Neurosci. 35 (47) (2015) 15731–15745

Börger V, Bremer M, Ferrer-tur R, Gockeln L, Stambouli O. Mesenchymal Stem / Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents. 2017;

R. Narayanan, C.C. Huang, S. Ravindran, Hijacking the cellular mail: exosome mediated differentiation of mesenchymal stem cells, Stem Cell. Int. 2016 (2016) 3808674.

K. McNicholas, M.Z. Michael, Immuno-characterization of exosomes using nanoparticle tracking analysis, Methods Mol. Biol. 1545 (2017) 35–42.

DOI: https://doi.org/10.26618/aimj.v1i2.2756


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