Acta Scientific Ophthalmology (ISSN: 2582-3191)

Research Article Volume 5 Issue 8

Improvement of Photoreceptor Function Following Transplantation of NS-Derived RPE Cells into the Subretinal Space of an Animal (Rat) Model of Retinal Degeneration

Hamid Aboutaleb Kadkhodaeian1,2, Taki Tiraihi1*, Hamid Ahmadieh3, Hossein Ziaei3, Narsis Daftarian4 and Taher Taheri5

1Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
2Department of Anatomical Sciences, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
3Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
5Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Rashid Yasemi Street, Tehran, Iran

*Corresponding Author: Taki Tiraih, Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Received: June 22, 2022; Published: July 19, 2022

Abstract

Purpose: To investigate transplantation of retinal pigment epithelium (RPE) antigen (PSRA)-expressing pigmented spheres in an animal (rat) model of age-related macular degeneration (AMD) using sodium iodate to rescue and improve (i) a- and b-wave activities, (ii) alter outer nuclear layer thickness, and (iii) enhance cell number.

Materials and Methods: Male hooded rats (n = 65) were divided into five groups, two of which received sodium iodate and three of which did not. AMD was induced using retro-orbital sodium iodate injection. After 30 days, cells were injected into the subretinal space using a trans-scleral approach. For cell transplantation, rat bone marrow stromal stem cells were differentiated into neurospheres (NSs) and, after 7 days, into RPE cells. For tracking, differentiated cells were labeled with BrdU and then transplanted into the subretinal space. Photoreceptor function was evaluated by full-field electroretinography over the course of 7-90 days. The effects of transplanted cells on neurosensory retina and RPE layer were assessed using immunohistochemistry and cresyl violet staining at corresponding time points.

Results: Both the scotopic b-wave at an intensity of 0.01 cd.s/m2 and photopic a-wave at an intensity of 3.0 cd.s/m2 were affected. Significant differences between the test groups and relevant controls appeared at 60 days, but only for the scotopic assay and, at 90 days, for the photopic assay. Seven days after injection, light microscopy of IHC on paraffin sections in the transplanted group showed that PSRA cells had migrated and integrated into the host RPE layers. Further investigation using specific RPE cell protein RPE65 and ZO-1 revealed that these cells were able to express specific proteins as well. There was a statistically significant difference between the numbers of outer nuclear layer (ONL) cells and thicknesses in transplanted group. Significant differences between the test group and relevant controls appeared throughout the 7-90 day course in ONL cell count and through 14-90 days in ONL thickness. Ninety days after transplantation, the RPE layer and the neurosensory retinal layers were detectable. There was a surprising affinity between the PSRA cells and the host RPE layer.

Discussion: We demonstrated that PSRA migrated into the subretinal space and integrated into the host layer, expressing ZO-1, and RPE65 markers. Additionally, we showed that photoreceptor activity improved. The ONL was thicker, and ONL cell numbers were better preserved than in RPE-damaged rats that received only phosphate buffered saline (PBS).

Keywords: Photoreceptor Function; RPE; Subretinal Space; Sodium Iodate; Rat BMSCsc

References

  1. Chan CM., et al. “Reactive oxygen species-dependent mitochondrial dynamics and autophagy confer protective effects in retinal pigment epithelial cells against sodium iodate-induced cell death”. Journal of Biomedical Science1 (2019): 40.
  2. Gong J., et al. “Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions”. Stem Cells Translational Medicine3 (2020): 364-376.
  3. Chen X., et al. “Unstimulated, serum-free cultures of retinal pigment epithelium excrete large mounds of drusen-like deposits”. Current Eye Research (2020): 1-5.
  4. Fields MA., et al. “Extracellular matrix nitration alters growth factor release and activates bioactive complement in human retinal pigment epithelial cells”. PloS One 5 (2017).
  5. Fields M., et al. “Interactions of the choroid, Bruch’s membrane, retinal pigment epithelium, and neurosensory retina collaborate to form the outer blood-retinal-barrier”. Progress in Retinal and Eye Research (2019): 100803.
  6. Naylor A., et al. “Tight junctions of the outer blood retina barrier”. International Journal of Molecular Sciences1 (2020): 211.
  7. Blenkinsop TA., et al. “Human adult retinal pigment epithelial stem cell–derived RPE monolayers exhibit key physiological characteristics of native tissue”. Investigative Ophthalmology and Visual Science 12 (2015): 7085-7099.
  8. Du W., et al. “Protection of kaempferol on oxidative stress-induced retinal pigment epithelial cell damage”. Oxidative Medicine and Cellular Longevity 2018 (2018).
  9. Zhu D., et al. “Protective effects of human iPS-derived retinal pigmented epithelial cells on retinal degenerative disease”. Stem Cell Research and Therapy1 (2020): 1-15.
  10. Park SS., et al. “Advances in bone marrow stem cell therapy for retinal dysfunction”. Progress in Retinal and Eye Research 56 (2017): 148-165.
  11. Kadkhodaeian HA., et al. “Generation of Retinal Pigmented Epithelium-Like Cells from Pigmented Spheres Differentiated from Bone Marrow Stromal Cell-Derived Neurospheres”. Tissue Engineering and Regenerative Medicine3 (2019): 253-263.
  12. Kadkhodaeian HA., et al. “High efficient differentiation of human adipose-derived stem cells into retinal pigment epithelium-like cells in medium containing small molecules inducers with a simple method”. Tissue and Cell6 (2019): 52-59.
  13. Aboutaleb HK., et al. “Survival and Migration of Adipose-Derived Stem Cells Transplanted in the Injured Retina”. Experimental and Clinical Transplantation: Official Journal of the Middle East Society for Organ Transplantation (2017).
  14. Koster C., et al. “A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models”. International Journal of Molecular Sciences8 (2020): 2719.
  15. Kadkhodaeian HA., et al. “Histological and electrophysiological changes in the retinal pigment epithelium after injection of sodium iodate in the orbital venus plexus of pigmented rats”. Journal of Ophthalmic and Vision Research1 (2016): 70.
  16. Qi Y., et al. “Trans-corneal subretinal injection in mice and its effect on the function and morphology of the retina”. PLoS One8 (2015).
  17. Liu Y., et al. “Morphologic and histopathologic change of sodium iodate-induced retinal degeneration in adult rats”. International Journal of Clinical and Experimental Pathology2 (2019): 443.
  18. Ma J., et al. “Combining chondroitinase ABC and growth factors promotes the integration of murine retinal progenitor cells transplanted into Rho−/− mice”. Molecular Vision 17 (2011): 1759.
  19. Imitola J., et al. “Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway”. Proceedings of the National Academy of Sciences52 (2004): 18117-18122.
  20. Kaarniranta K., et al. “Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration”. Progress in Retinal and Eye Research (2020): 100858.
  21. Lin TC., et al. “Assessment of safety and functional efficacy of stem cell-based therapeutic approaches using retinal degenerative animal models”. Stem Cells International 2017 (2017).
  22. Lund RD., et al. “Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease”. Stem Cells3 (2007): 602-611.
  23. Puertas-Neyra K., et al. “Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative diseases”. Neural Regeneration Research9 (2020): 1631.
  24. Tzameret A., et al. “Epiretinal transplantation of human bone marrow mesenchymal stem cells rescues retinal and vision function in a rat model of retinal degeneration”. Stem Cell Research2 (2015): 387-394.
  25. Comyn O., et al. “Induced pluripotent stem cell therapies for retinal disease”. Current Opinion in Neurology1 (2010): 4.
  26. Harvey JP., et al. “Induced Pluripotent Stem Cells for Inherited Optic Neuropathies-Disease Modeling and Therapeutic Development”. Journal of Neuro-ophthalmology: The Official Journal of the North American Neuro-ophthalmology Society (2021).
  27. Marchetti V., et al. “Stemming vision loss with stem cells”. The Journal of Clinical Investigation9 (2010): 3012-3021.
  28. Park SJ., et al. “Convergence and divergence of CRH amacrine cells in mouse retinal circuitry”. Journal of Neuroscience 38 (15): 3753-3766.
  29. Hu C., et al. “Transplantation Site Affects the Outcomes of Adipose-Derived Stem Cell-Based Therapy for Retinal Degeneration”. Stem Cells International 2020 (2020).
  30. Huang H., et al. “Intravitreal injection of mesenchymal stem cells evokes retinal vascular damage in rats”. The FASEB Journal12 (2019): 14668-14679.
  31. Duan P., et al. “Comparison of protective effects of hESCs-derived and hBMSCs-derived RPE cells on sodium iodate-injuried rat retina”. International Journal of Clinical and Experimental Pathology5 (2017): 5274-5284.
  32. Saszik SM., et al. “The scotopic threshold response of the dark‐adapted electroretinogram of the mouse”. The Journal of Physiology3 (2002): 899-916.
  33. Panse M. “Analysis of bioelectrical signal of the human retina (ERG) using LabVIEW”. in 2010 IEEE Students Technology Symposium (TechSym). IEEE (2010).
  34. Zhai W., et al. “Combined transplantation of olfactory ensheathing cells with rat neural stem cells enhanced the therapeutic effect in the retina of RCS rats”. Frontiers in Cellular Neuroscience 14 (2020): 52.
  35. Robson J., et al. “In vivo studies of signaling in rod pathways of the mouse using the electroretinogram”. Vision Research28 (2004): 3253-3268.
  36. Perlman I. “The electroretinogram: ERG”. in Webvision: The Organization of the Retina and Visual System. 2007, University of Utah Health Sciences Center (2007).
  37. Demb JB and JH Singer. “Functional circuitry of the retina”. Annual Review of Vision Science 1 (20195): 263-289.
  38. Chacko DM., et al. “Transplantation of ocular stem cells: the role of injury in incorporation and differentiation of grafted cells in the retina”. Vision Research8 (2003): 937-946.
  39. Chen X., et al. “Adult limbal neurosphere cells: a potential autologous cell resource for retinal cell generation”. Plos One10 (2014).
  40. Hertz J., et al. “Survival and integration of developing and progenitor-derived retinal ganglion cells following transplantation”. Cell Transplantation7 (20194): 855-872.
  41. Tomita, M., et al. “Bone marrow‐derived stem cells can differentiate into retinal cells in injured rat retina”. Stem Cells4 (2002): 279-283.
  42. Zhang Y and W Wang. “Effects of bone marrow mesenchymal stem cell transplantation on light-damaged retina”. Investigative Ophthalmology and Visual Science7 (2010): 3742-3748.
  43. Stern JH and S Temple. “Stem cells for retinal replacement therapy”. Neurotherapeutics4 (2011): 736-743.
  44. Park UC., et al. “Subretinal transplantation of putative retinal pigment epithelial cells derived from human embryonic stem cells in rat retinal degeneration model”. Clinical and Experimental Reproductive Medicine4 (2011): 216-221.
  45. Lund RD., et al. “Subretinal transplantation of genetically modified human cell lines attenuates loss of visual function in dystrophic rats”. Proceedings of the National Academy of Sciences17 (2001): 9942-9947.
  46. Lund RD., et al. “Human embryonic stem cell–derived cells rescue visual function in dystrophic RCS rats”. Cloning and Stem Cells3 (2006): 189-199.
  47. Lu B., et al. “Neural stem cells derived by small molecules preserve vision”. Translational Vision Science and Technology 1 (2013): 1-1.
  48. Huang R., et al. “Functional and morphological analysis of the subretinal injection of human retinal progenitor cells under Cyclosporin A treatment”. Molecular Vision 20 (2014): 1271.
  49. Harris JR., et al. Stem Cells2 (2011): 457-466.
  50. Chung JK., et al. “Modulation of retinal wound healing by systemically administered bone marrow-derived mesenchymal stem cells”. Korean Journal of Ophthalmology4 (2011): 268-274.

Citation

Citation: Taki Tiraihi., et al. “Improvement of Photoreceptor Function Following Transplantation of NS-Derived RPE Cells into the Subretinal Space of an Animal (Rat) Model of Retinal Degeneration".Acta Scientific Ophthalmology 5.8 (2022): 29-49.

Copyright

Copyright: © 2022 Taki Tiraihi., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.




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