Retinal Ganglion Cells - Forthcoming Restoration of Epigenetically Induced Damage

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 Forthcoming Restoration of Epigenetically Induced Damage
to Retinal Ganglion Cells

Retinal ganglion cell degeneration is one the baseis for a number of ocular neuropathies and diseases, including glaucoma (Corral-Domenge, 2022; Khatib & Martin, 2017; Munemasa & Kitaoka, 2013). As of 2019, 2.2 billion people are blind or have visual problems (World Health Organization, 2019), according to SEE International (2022), 76 million people will suffer from glaucoma, and it is predicted that there will be a 74% increase in glaucoma the next 20 years. A number of causes for retinal ganglion cell degeneration have been proposed that also include immune dysfunction, reactive oxygen species (ROS), and mitochondrial pathology (Munemasa & Kitaoka, 2013). There are currently no approved cures for retinal ganglion cell degradation in glaucoma cases, the standard treatment being lowering of intraocular pressure to assist in preventing further damage (Khatib & Martin, 2017; Munemasa & Kitaoka, 2013). New oral and optic pharmaceuticals are being investigated but have yet to be solidly proven for continued human intervention. Stem cell and gene therapy studies are currently in early to mid trial phases (Khatib & Martin, 2017). 

Stem cell treatment may not be enough as there are recent indications that although it is true, stem cell treatments do help prevent further damage and initiate partial restoration of retinal ganglion cells, stem cell treatments alone may not be sufficient for complete regeneration in complex diseases like glaucoma. The good news is there have been major findings regarding gene expression and epigenomics. Discoveries include the realization that disruption in normal gene expression is indicated in retinal ganglion cell degeneration and that refreshing epigenetic markers to normal states can assist in revitalize these cells. In related experiments, it was found that rod degeneration in rodents could be stopped by inhibiting histone demethylases and histone deacetylases, a result along with others regarding epigenetics that is about to propel us into an new molecular age that entails a epigenetic paradigm shift related to disease origination and intervention (Barnstable, 2022). 

Three epigenetic mechanisms in particular have been and are being studied extensively in relation to how they can cause disease through improper expression of genes. In particular these epigenetic modifications include, but are not limited to, DNA methylation, changes to histone tagging (acetylation, methylation, and phosphorylation), and regulation by noncoding ribonucleic acids (nRNAs). Depending on the modifier, and modification and type of target, epigenetic controls can drive or diminish gene expression. Hindrance of these controls can cause drastic detrimental changes to cell development and viability (Barnstable, 2022; Lu et al. 2020). Multiple studies show that over-methylation increases deleterious effects on optical structures including retinal components, inhibits tumor suppressor genes, and seems to be a common cause in degenerative diseases including retinal membrane dysfunction (Barnstable, 2022). 

In 2020, Lu et al., (2020) thoroughly reconfirmed that epigenetic changes affect the health and well being of retinal ganglion cells and play a significant part in their degeneration. In addition to epigenetic control confirmation, they used three of four Yamanaka transcription factors (Oct4, Sox2, Klf4 - [OSK]) to show that by epigenetically refreshing mammalian retinal ganglion cells, the cell epigenomes could be returned to their youthful condition, including the original epigenetic tagging that established cell identity. In addition, their study established that optic axons could be regenerated by the methods used (Lu et al., 2020). The reason for using the three Yamanaka transcription factors, of which there are four (Oct4, Sox2, Klf4, and c-Myc [OSKM]), was that they had been used previously to create pluripotent stem cells from somatic cells (Takahashi & Yamanaka, 2006; as cited in Lu et al., 2020; Simpson et al., 2021). Additionally, Luet al. (2020) proved that the axon density in glaucomatous eyes receiving the OSK treatment were restored, comparative to pre-glaucomatous eyes, and did not show any signs of excessive proliferation. Remarkably, in their study vision was restored in mice in vivo, possibly being the first time that site was ever restored in this manner. 

Further studies are progressing in the area of cell reprogramming to youthful states (Ashok et al., 2022; de Lima Camillo & Quinlan, 2021; Simpson, 2021; Xiao et al., 2021; Zhang et al., 2020) The most prominent  remaining safety barrier is to nullify the risk of cancer when using epigenetic methods to regenerate cells, tissues, and animals. An exciting concept that has emerged in cellular reprogramming is to regenerate cells to the point where epigenetics is restored to a normal state just after cell identity is established. Methods of this nature that strive for this level of dedifferentiation may likely be how we prevent negative outcomes such as excessive proliferation, and thus cancer. Establishing how far to revert a cell epigenome to establish a safe window is the basis of this pursuit (Simpson, 2021).

     In closing, this post is not about the ethical considerations of youthful regeneration, however, it is proper to note that rational and legitimate ethical consideration should be used in any experiment involving humans, as was established many years ago. An excellent delineation of ethics in experimentation titled, "Five Principles for Research Ethics: Cover your Bases with these Ethical Strategies" can be found on the American Psychological website at https://www.apa.org/monitor/jan03/principles (Smith, 2003). 

 

References

Ashok, A., Pooranawattanakul, S., Tai, W.L., Cho, K.S., Utheim, T.P., Cestari, D.M., & Chen, D.F. (2022). Epigenetic Regulation of Optic Nerve Development, Protection, and Repair. International Journal of Molecular Sciences, 23(16), 8927. doi.org/10.3390/ijms23168927

Barnstable C.J. (2022). Epigenetics and Degenerative Retinal Diseases: Prospects for New Therapeutic Approaches. Asia-Pacific Journal of Ophthalmology, 11(4), 328–334. doi.org/10.1097/APO.0000000000000520

Corral-Domenge, C., de la Villa, P., Mansilla, A., & Germain, F. (2022). Tools and Biomarkers for the Study of Retinal Ganglion Cell Degeneration. International Journal of Molecular Sciences, 23(8), 4287. doi.org/10.3390/ijms23084287

de Lima Camillo, L. P., & Quinlan, R. (2021). A ride through the epigenetic landscape: aging reversal by reprogramming. GeroScience, 43(2), 463–485. https://doi.org/10.1007/s11357-021-00358-6

Khatib, T.Z., & Martin, K.R. (2017). Protecting Retinal Ganglion Cells. Eye, 31(2), 218–224. doi.org/10.1038/eye.2016.299

Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D.L., Zeng, Q., Yu, D., Bonkowski, M.S., Yang, J.H., Zhou, S., Hoffmann, E.M., Karg, M.M., Schultz, M.B., Kane, A.E., Davidsohn, N., Korobkina, E., Chwalek, K., Rajman, L.A., Church, G.M., Hochedlinger, K., Gladyshev, V.N., Horvath, S., Levine, M.E., Gregory-Ksander, M.S., Ksander, B.R., He, Z., Sinclair, D.A. (2020). Reprogramming to Recover Youthful Epigenetic Information and Restore Vision. Nature, 588(7836), 124-129. doi: 10.1038/s41586-020-2975-4

SEE International. (2022) Glaucoma. Retrieved on October 22, 2022 from https://www.seeintl.org/glaucoma/ 

World Health Organization. (2019). World Report on Vision. WHO. Retrieved on October 22, 2022 from https://www.who.int/publications/i/item/9789241516570

Munemasa, Y., & Kitaoka, Y. (2013). Molecular Mechanisms of Retinal Ganglion Cell Degeneration in Glaucoma and Future Prospects for Cell Body and Axonal protection. Frontiers in Cellular Neuroscience, 6, 60. doi.org/10.3389/fncel.2012.00060

Simpson, D.J., Olova, N. N., & Chandra, T. (2021). Cellular Reprogramming and Epigenetic Rejuvenation. Clinical Epigenetics, 13(1), 170. doi.org/10.1186/s13148-021-01158-7

Smith, D. (2003). Five Principles for Research Ethics: Cover your Bases with these Ethical Strategies. American Psychological Association. Retrieved on October 23, 2022 from https://www.apa.org/monitor/jan03/principles

Takahashi, K., & Yamanaka, S. (2006). Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, 126(4), 663–676. doi.org/10.1016/j.cell.2006.07.024

Xiao, D., Jin, K., Qiu, S., Lei, Q., Huang, W., Chen, H., Su, J., Xu, Q., Xu, Z., Gou, B., Tie, X., Liu, F., Liu, S., Liu, Y., & Xiang, M. (2021). In Vivo Regeneration of Ganglion Cells for Vision Restoration in Mammalian Retinas. Frontiers in Cell and Developmental Biology, 9, 755544. doi.org/10.3389/fcell.2021.755544

Zhang, W., Qu, J., Liu, G.H., & Belmonte, J. (2020). The Ageing Epigenome and its Rejuvenation. Molecular Cell Biology, 21(3), 137–150. doi.org/10.1038/s41580-019-0204-5



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