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Graefe's Archive for Clinical and Experimental Ophthalmology

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01-08-2017 | Basic Science

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

Authors: Biji Mathew, Jacqueline N. Poston, John C. Dreixler, Leianne Torres, Jasmine Lopez, Ruth Zelkha, Irina Balyasnikova, Maciej S. Lesniak, Steven Roth

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 8/2017

Abstract

Purpose

Ischemia-associated retinal degeneration is one of the leading causes of vision loss, and to date, there are no effective treatment options. We hypothesized that delayed injection of bone-marrow stem cells (BMSCs) 24 h after the onset of ischemia could effectively rescue ischemic retina from its consequences, including apoptosis, inflammation, and increased vascular permeability, thereby preventing retinal cell loss.

Methods

Retinal ischemia was induced in adult Wistar rats by increasing intraocular pressure (IOP) to 130–135 mmHg for 55 min. BMSCs harvested from rat femur were injected into the vitreous 24 h post-ischemia. Functional recovery was assessed 7 days later using electroretinography (ERG) measurements of the a-wave, b-wave, P2, scotopic threshold response (STR), and oscillatory potentials (OP). The retinal injury and anti-ischemic effects of BMSCs were quantitated by measuring apoptosis, autophagy, inflammatory markers, and retinal–blood barrier permeability. The distribution and fate of BMSC were qualitatively examined using real-time fundus imaging, and retinal flat mounts.

Results

Intravitreal delivery of BMSCs significantly improved recovery of the ERG a- and b-waves, OP, negative STR, and P2, and attenuated apoptosis as evidenced by decreased TUNEL and caspase-3 protein levels. BMSCs significantly increased autophagy, decreased inflammatory mediators (TNF-α, IL-1β, IL-6), and diminished retinal vascular permeability. BMSCs persisted in the vitreous and were also found within ischemic retina.

Conclusions

Taken together, our results indicate that intravitreal injection of BMSCs rescued the retina from ischemic damage in a rat model. The mechanisms include suppression of apoptosis, attenuation of inflammation and vascular permeability, and preservation of autophagy.

Al-Shabrawey M, Rojas M, Sanders T, Behzadian A, El-Remessy A, Bartoli M, Parpia AK, Liou G, Caldwell RB (2008) Role of NADPH oxidase in retinal vascular inflammation. Invest Ophthalmol Vis Sci 49:3239–3244CrossRefPubMedPubMedCentral

Hangai M, Yoshimura N, Honda Y (1996) Increased cytokine gene expression in rat retina following transient ischemia. Ophthalmic Res 28:248–254CrossRefPubMed

Gustavsson C, Agardh C-D, Hagert P, Agardh E (2008) Inflammatory markers in nondiabetic and diabetic rat retinas exposed to ischemia followed by reperfusion. Retina 28:645–652CrossRefPubMed

Abcouwer SF, Lin CM, Wolpert EB, Shanmugam S, Schaefer EW, Freeman WM, Barber AJ, Antonetti DA (2010) Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci 51:5920–5933. doi:10.1167/iovs.10-5264 CrossRefPubMed

Osborne NN, Casson RJ, Wood JPM, Chidlow G, Graham M, Melena J (2004) Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res 23:91–147CrossRefPubMed

Dattilo M, Biousse V, Newman NJ (2017) Update on the management of central retinal artery occlusion. Neurol Clin 35:83–100. doi:10.1016/j.ncl.2016.08.013 CrossRefPubMed

Park SS, Moisseiev E, Bauer G, Anderson JD, Grant MB, Zam A, Zawadzki RJ, Werner JS, Nolta JA (2017) Advances in bone marrow stem cell therapy for retinal dysfunction. Prog Retin Eye Res 56:148–165. doi:10.1016/j.preteyeres.2016.10.002 CrossRefPubMed

Sun J, Wei ZZ, Gu X, Zhang JY, Zhang Y, Li J, Wei L (2015) Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice. Exp Neurol 272:78–87 http://dx.doi.org/10.1016/j.expneurol.2015.03.011 CrossRefPubMed

Roth S, Dreixler JC, Mathew B, Balyasnikova I, Mann JR, Boddapati V, Xue L, Lesniak MS (2016) Hypoxic-preconditioned bone marrow stem cell medium significantly improves outcome after retinal ischemia in RatsPreconditioned stem cells and retinal ischemia. Invest Ophthalmol Vis Sci 57:3522–3532. doi:10.1167/iovs.15-17381 CrossRefPubMedPubMedCentral

10.

Li N, X-r L, J-q Y (2009) Effects of bone-marrow mesenchymal stem cells transplanted into vitreous cavity of rat injured by ischemia/reperfusion. Graefes Arch Clin Exp Ophthalmol 247:503–514CrossRefPubMed

11.

Zheng L, Gong B, Hatala DA, Kern TS (2007) Retinal ischemia and reperfusion causes capillary degeneration: similarities to diabetes. Invest Ophthalmol Vis Sci 48:361–367CrossRefPubMed

12.

Dowling JE (1963) Neural and photochemical mechanisms of visual adaptation in the rat. J Gen Physiol 46:1287–1301CrossRefPubMedPubMedCentral

13.

Roth S, Shaikh AR, Hennelly MM, Li Q, Bindokas V, Graham CE (2003) Mitogen-activated protein kinases and retinal ischemia. Invest Ophthalmol Vis Sci 44:5383–5395CrossRefPubMed

14.

Roth S, Dreixler JC, Shaikh AR, Lee KH, Bindokas V (2006) Mitochondrial potassium ATP channels and retinal ischemic preconditioning. Invest Ophthalmol Vis Sci 47:2114–2124CrossRefPubMedPubMedCentral

15.

Dreixler JC, Shaikh AR, Shenoy SK, Shen Y, Roth S (2008) Protein kinase C subtypes and retinal ischemic preconditioning. Exp Eye Res 87:300–311CrossRefPubMedPubMedCentral

16.

Dreixler JC, Poston JN, Balyasnikova I, Shaikh AR, Lesniak MS, Roth S (2014) Delayed administration of bone marrow mesenchymal stem cell conditioned medium significantly improves outcome after retinal ischemia in rats. Invest Ophthalmol Vis Sci 55:3785–3796. doi:10.1167/iovs.13-11683 CrossRefPubMedPubMedCentral

17.

Weymouth AE, Vingrys AJ (2008) Rodent electroretinography: methods for extraction and interpretation of rod and cone responses. Prog Retin Eye Res 27:1–44CrossRefPubMed

18.

Bui BV, Edmunds B, Cioffi GA, Fortune B (2005) The gradient of retinal functional changes during acute intraocular pressure elevation. Invest Ophthalmol Vis Sci 46:202–213CrossRefPubMed

19.

Singh M, Savitz SI, Hoque R, Rosenbaum PS, Roth S, Rosenbaum DM (2001) Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia. J Neurochem 77:466–475CrossRefPubMed

20.

Zhang C, Rosenbaum DM, Shaikh AR, Li Q, Rosenbaum PS, Pelham DJ, Roth S (2002) Ischemic preconditioning attenuates apoptosis following retinal ischemia in rats. Invest Ophthalmol Vis Sci 43:3059–3066PubMed

21.

Huang C, Andres AM, Ratliff EP, Hernandez G, Lee P, Gottlieb RA (2011) Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS One 6:e20975. doi:10.1371/journal.pone.0020975 CrossRefPubMedPubMedCentral

22.

Carloni S, Girelli S, Scopa C, Buonocore G, Longini M, Balduini W (2015) Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia–ischemia. Autophagy 6:366–377CrossRef

23.

Fang IM, Yang C-M, Yang C-H, Chiou S-H, Chen M-S (2013) Transplantation of induced pluripotent stem cells without C-Myc attenuates retinal ischemia and reperfusion injury in rats. Exp Eye Res 113:49–59. doi:10.1016/j.exer.2013.05.007 CrossRefPubMed

24.

Goncalves A, Lin CM, Muthusamy A, Fontes-Ribeiro C, Ambrosio AF, Abcouwer SF, Fernandes R, Antonetti DA (2016) Protective effect of a GLP-1 analog on ischemia-reperfusion induced blood–retinal barrier breakdown and inflammation. Invest Ophthalmol Vis Sci 57:2584–2592. doi:10.1167/iovs.15-19006 CrossRefPubMedPubMedCentral

25.

Dreixler JC, Poston JN, Shaikh AR, Alexander M, Tupper KY, Marcet MM, Bernaudin M, Roth S (2011) Delayed post-ischemic conditioning significantly improves the outcome after retinal ischemia. Exp Eye Res 92:521–527CrossRefPubMed

26.

Fortune B, Bui BV, Morrison JC, Johnson EC, Dong J, Cepurna WO, Jia L, Barber S, Cioffi GA (2004) Selective ganglion cell functional loss in rats with experimental glaucoma. Invest Ophthalmol Vis Sci 45:1854–1862CrossRefPubMed

27.

Schlamp CL, Johnson EC, Li Y, Morrison JC, Nickells RW (2001) Changes in Thy1 gene expression associated with damaged retinal ganglion cells. Mol Vis 7:192–201PubMed

28.

Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E (2005) Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1:84–91CrossRefPubMed

29.

Feng Y, Yao Z, Klionsky DJ (2015) How to control self-digestion: transcriptional, post-transcriptional, and post-translational regulation of autophagy. Trends Cell Biol. doi:10.1016/j.tcb.2015.02.002 PubMedPubMedCentral

30.

Saftig P, Beertsen W, Eskelinen EL (2008) LAMP-2: a control step for phagosome and autophagosome maturation. Autophagy 4:510–512CrossRefPubMed

31.

Johnson TV, Bull ND, Martin KR (2010) Identification of barriers to retinal engraftment of transplanted stem cells. Invest Ophthalmol Vis Sci 51:960–970CrossRefPubMedPubMedCentral

32.

Reichenbach A, Wurm A, Pannicke T, Iandiev I, Wiedemann P, Bringmann A (2007) Muller cells as players in retinal degeneration and edema. Graefes Arch Clin Exp Ophthalmol 245:627–636CrossRefPubMed

33.

Uckermann O, Kutzera F, Wolf A, Pannicke T, Reichenbach A, Wiedemann P, Wolf S, Bringmann A (2005) The glucocorticoid triamcinolone acetonide inhibits osmotic swelling of retinal glial cells via stimulation of endogenous adenosine signaling. J Pharmacol Exp Ther 315:1036–1045CrossRefPubMed

34.

Dreixler JC, Barone FC, Shaikh AR, Du E, Roth S (2009) Mitogen-activated protein kinase p38alpha and retinal ischemic preconditioning. Exp Eye Res 89:782–790CrossRefPubMedPubMedCentral

35.

Dreixler JC, Hemmert JW, Shenoy SK, Shen Y, Lee HT, Shaikh AR, Rosenbaum DM, Roth S (2009) The role of Akt/protein kinase B subtypes in retinal ischemic preconditioning. Exp Eye Res 88:512–521CrossRefPubMed

36.

Dreixler J, Shaikh A, Alexander M, Savoie B, Roth S (2010) Post-ischemic conditioning in the rat retina is dependent upon ischemia duration and is not additive with ischemic preconditioning. Exp Eye Res 91:844–852CrossRefPubMedPubMedCentral

37.

Jo N, Wu G-S, Rao NA (2003) Upregulation of chemokine expression in the retinal vasculature in ischemia-reperfusion injury. Invest Ophthalmol Vis Sci 44:4054–4060CrossRefPubMed

38.

Hattori T, Hayashi H, Chiba T, Onozaki K (2001) Activation of two distinct anti-proliferative pathways, apoptosis and p38 MAP kinase-dependent cell cycle arrest, by tumor necrosis factor in human melanoma cell line A375. Eur Cytokine Netw 12(2):244–252PubMed

39.

Danesh-Meyer HV, Kerr NM, Zhang J, Eady EK, O'Carroll SJ, Nicholson LFB, Johnson CS, Green CR (2012) Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia. Brain 135:506–520. doi:10.1093/brain/awr338 CrossRefPubMed

40.

Peng J, Drobish JK, Liang G, Wu Z, Liu C, Joseph DJ, Abdou H, Eckenhoff MF, Wei H (2014) Anesthetic preconditioning inhibits isoflurane-mediated apoptosis in the developing rat brain. Anesth Analg 119:939–946. doi:10.1213/ane.0000000000000380 CrossRefPubMedPubMedCentral

41.

Feng Y, Rhodes PG, Bhatt AJ (2015) Hypoxic preconditioning provides neuroprotection and increases vascular endothelial growth factor a, preserves the phosphorylation of Akt-Ser-473 and diminishes the increase in caspase-3 activity in neonatal rat hypoxic-ischemic model. Brain Res 1325:1–9CrossRef

42.

Amato R, Biagioni M, Cammalleri M, Dal Monte M, Casini G (2016) VEGF as a survival factor in ex vivo models of early diabetic retinopathy. Invest Ophthalmol Vis Sci 57:3066–3076. doi:10.1167/iovs.16-19285 CrossRefPubMed

43.

Nakahara T, Hoshino M, Hoshino S, Mori A, Sakamoto K, Ishii K (2015) Structural and functional changes in retinal vasculature induced by retinal ischemia-reperfusion in rats. Exp Eye Res 135:134–145. doi:10.1016/j.exer.2015.02.020 CrossRefPubMed

44.

Piras A, Gianetto D, Conte D, Bosone A, Vercelli A (2011) Activation of autophagy in a rat model of retinal ischemia following high intraocular pressure. PLoS One 6:e22514. doi:10.1371/journal.pone.0022514; CrossRefPubMedPubMedCentral

45.

Russo R, Berliocchi L, Adornetto A, Varano GP, Cavaliere F, Nucci C, Rotiroti D, Morrone LA, Bagetta G, Corasaniti MT (2011) Calpain-mediated cleavage of Beclin-1 and autophagy deregulation following retinal ischemic injury in vivo. Cell Death Dis 2:e144. doi:10.1038/cddis.2011.29 CrossRefPubMedPubMedCentral

46.

Wang G, Zhou D, Wang C, Gao Y, Zhou Q, Qian G, DeCoster MA (2010) Hypoxic preconditioning suppresses group III secreted phospholipase A2-induced apoptosis via JAK2-STAT3 activation in cortical neurons. J Neurochem 114:1039–1048. doi:10.1111/j.1471-4159.2010.06817.x PubMed

47.

Tang X, Tzekov R, Passaglia CL (2016) Retinal cross talk in the mammalian visual system. J Neurophysiol 115:3018–3029. doi:10.1152/jn.01137.2015 CrossRefPubMedPubMedCentral

Title: Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats
Authors: Biji Mathew
Jacqueline N. Poston
John C. Dreixler
Leianne Torres
Jasmine Lopez
Ruth Zelkha
Irina Balyasnikova
Maciej S. Lesniak
Steven Roth
Publication date: 01-08-2017
Publisher: Springer Berlin Heidelberg
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 8/2017
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-017-3690-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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