Retinal regeneration refers to the restoration of vision in vertebrates that have suffered retinal lesions or retinal degeneration.
The two most well-studied mechanisms of retinal regeneration are cell-mediated regeneration and cellular transplantation. Regenerative processes may have applications in humans for treating degenerative retinal diseases, such as retinitis pigmentosa. While mammals, such as humans and mice, lack the innate ability to regenerate the retina, lower vertebrates, such as teleost fish and salamanders, are capable of regenerating lost retinal tissue in the event of damage.
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Could a blind eye regenerate? - David Davila
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Vision Research: Breakthroughs & Clinical Care
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AGI Workshop Report to National Advisory Eye Council June 16, 2016
Transcription
Imagine that day by day, your field of vision becomes slightly smaller, narrowing or dimming until eventually you go completely blind. We tend to think of blindness as something you're born with, but in fact, with many diseases like Retinitis pigmentosa and Usher syndrome, blindness can start developing when you're a kid, or even when you're an adult. Both of these rare genetic diseases affect the retina, the screen at the back of the eye that detects light and helps us see. Now imagine if the eye could regenerate itself so that a blind person could see again. To understand if that's possible, we need to grasp how the retina works and what it has to do with a multitalented creature named the zebrafish. The human retina is made of different layers of cells, with special neurons that live in the back of the eye called rod and cone photoreceptors. Photoreceptors convert the light coming into your eye into signals that the brain uses to generate vision. People who have Usher syndrome and retinitis pigmentosa experience a steady loss of these photoreceptors until finally that screen in the eye can no longer detect light nor broadcast signals to the brain. Unlike most of your body's cells, photoreceptors don't divide and multiply. We're born with all the photoreceptors we'll ever have, which is why babies have such big eyes for their faces and part of why they're so cute. But that isn't the case for all animals. Take the zebrafish, a master regenerator. It can grow back its skin, bones, heart and retina after they've been damaged. If photoreceptors in the zebrafish retina are removed or killed by toxins, they just regenerate and rewire themselves to the brain to restore sight. Scientists have been investigating this superpower because zebrafish retina are also structured very much like human retina. Scientists can even mimic the effects of disorders like Usher syndrome or retinitis pigmentosa on the zebrafish eye. This allows them to see how zebrafish go about repairing their retinas so they might use similar tactics to fix human eyes one day, too. So what's behind the zebrafish's superpower? The main players are sets of long cells that stretch across the retina called Müller glia. When the photoreceptors are damaged, these cells transform, taking on a new character. They become less like Müller cells and more like stem cells, which can turn into any kind of cell. Then these long cells divide, producing extras that will eventually grow into new photoreceptors, travel to the back of the eye and rewire themselves into the brain. And now some researchers even think they've found the key to how this works with the help of one of two chemicals that create activity in the brain called glutamate and aminoadipate. In mouse eyes, these make the Müller glia divide and transform into photoreceptors, which then travel to the back of the retina, like they're replenishing a failing army with new soldiers. But remember, none of this has happened in our retinas yet, so the question is how do we trigger this transformation of the Müller glia in the human eye? How can we fully control this process? How do photoreceptors rewire themselves into the retina? And is it even possible to trigger this in humans? Or has this mechanism been lost over time in evolution? Until we tease apart the origins of this ability, retinal regeneration will remain a mysterious superpower of the common zebrafish.
By creature
In zebrafish
Zebrafish, like other teleost fish, possess the innate ability to regenerate retinal damage. This ability combined with the considerable similarity between teleost and mammalian retinal structure makes zebrafish an attractive model for the study of retinal regeneration.[1] Muller glia are a type of glial cell present in both the teleost and mammalian retina. Retinal regeneration in zebrafish is mediated by Muller glia, which dedifferentiate into stem-like cells and proliferate into neural progenitor cells in response to retinal damage. While Muller glia division is responsible for the regeneration of the retina in all cases of retinal damage, the case of photoreceptor loss due to light damage is particularly well characterized. In response to photoreceptor ablation, Muller glia dedifferentiate and undergo a single asymmetric division to produce a neural progenitor cell and a new Muller glia cell. The neural progenitor cell proliferates to form a cluster of neural progenitors, which migrate to the outer nuclear layer of the retina and differentiate into photoreceptors to replace the lost cells.[2] This process restores retinal function to the injured fish. Understanding the underlying mechanisms may provide insight into treatment options for degenerative retinal diseases in mammals.
Several proteins and signaling pathways have been described and characterized in the process of retinal regeneration. The roles of a few important elements are summarized below:[3][4][5][6][7]
| Protein | General Role | Role in Retinal Regeneration |
|---|---|---|
| TNF-a | induces inflammation, induces apoptosis | signals Muller glia to dedifferentiate |
| Notch | regulates differentiation and cell fate determination | maintains Muller glial quiescence |
| N-cadherin | mediates cell-cell interactions, stimulates axonal guidance | guides neural progenitor cell migration |
| Ascl1 | mediates neurogenesis | contributes to Muller glial dedifferentiation |
| β-catenin | actives the Wnt pathway | necessary for Muller glial proliferation |
Rod precursor differentiation is another mechanism by which zebrafish can replace lost retinal neurons. Rod precursors are produced during normal zebrafish growth and localize to the outer nuclear layer of the retina. In the event of chronic or small-scale rod photoreceptor death, rod precursors proliferate and differentiate into new rod photoreceptors.[8] This population of progenitor cells can be induced to proliferate by means such as injection of growth hormone or selective rod photoreceptor cell death. However, as this regenerative response is more limited than the Muller glia mediated response, much less is known about its underlying mechanisms.
In mice
Mice, like other mammals, do not show an innate capacity to regenerate retinal damage. Retinal damage in mammals instead typically results in gliosis and scar formation which interrupts normal retinal function. Previously, treating damaged eyes with epidermal growth factor induced Muller glia proliferation in the mouse eye, but neuron generation only occurred with concurrent overexpression of Ascl1.[9] More recently, robust Muller glia proliferation and subsequent neuronal differentiation has been seen using the alpha 7 nAChR agonist, PNU-282987.[10] More information on the signaling pathways involved is required before Muller glia mediated regeneration will be a viable treatment method for restoring vision in mammalian retinas.
Other approaches to retinal regeneration involve cellular transplantation treatments. In findings presented in the journal "Proceedings of the National Academy of Sciences" in 2012, a Nuffield Laboratory of Ophthalmology research team led by Dr Robert MacLaren from the University of Oxford restored sight to totally blind mice by injections of light-sensing cells into their eyes. The mice had suffered from a complete lack of photoreceptor cells in their retinas, and had been unable to tell light from dark. Promising results using the same treatment had been achieved with night-blind mice. Despite questions about the quality of restored vision, this treatment gives hope to people with dysfunctional vision and including degenerative eye diseases such as retinitis pigmentosa.
The procedure involved injecting rod precursors which formed an 'anatomically distinct and appropriately polarized outer nuclear layer' - two weeks later a retina had formed with restored connections and sight, proving that it was possible to reconstruct the entire light-sensitive layer. Researchers at Moorfields Eye Hospital had already been using human embryonic stem cells to replace the pigmented lining of the retina in patients with Stargardt's disease. The team is also restoring vision to blind patients with an electronic retinal implant which works on a similar principle of replacing the function of the light-sensing photoreceptor cells.
In humans
In February 2013, the US Food and Drug Administration approved the use of the Argus II Retinal Prosthesis System [1],[11] making it the first FDA-approved implant to treat retinal degeneration. The device may help adults with RP who have lost the ability to perceive shapes and movement to be more mobile and to perform day-to-day activities.
External links
References
- ^ Fadool, JM; Dowling, JE (2008). "Zebrafish: a model system for the study of eye genetics". Prog Retin Eye Res. 27 (1): 89–110. doi:10.1016/j.preteyeres.2007.08.002. PMC 2271117. PMID 17962065.
- ^ Gorsuch, RA; Hyde, DR (2014). "Regulation of Müller glial dependent neuronal regeneration in the damaged adult zebrafish retina". Exp Eye Res. 123: 131–40. doi:10.1016/j.exer.2013.07.012. PMC 3877724. PMID 23880528.
- ^ Ascl1a (2010). "let-7 microRNA signalling pathway -". Nature Cell Biology. 12 (11): 1101–1107. doi:10.1038/ncb2115. PMC 2972404. PMID 20935637.
{{cite journal}}: CS1 maint: numeric names: authors list (link) - ^ Wan, J; Ramachandran, R; Goldman, D (2012). "HB-EGF is necessary and sufficient for Müller glia dedifferentiation and retina regeneration". Dev Cell. 22 (2): 334–47. doi:10.1016/j.devcel.2011.11.020. PMC 3285435. PMID 22340497.
- ^ Nagashima, M; Barthel, LK; Raymond, PA (2013). "A self-renewing division of zebrafish Müller glial cells generates neuronal progenitors that require N-cadherin to regenerate retinal neurons". Development. 140 (22): 4510–21. doi:10.1242/dev.090738. PMC 3817940. PMID 24154521.
- ^ Conner, C; Ackerman, KM; Lahne, M; Hobgood, JS; Hyde, DR (2014). "Repressing notch signaling and expressing TNFα are sufficient to mimic retinal regeneration by inducing Müller glial proliferation to generate committed progenitor cells". J Neurosci. 34 (43): 14403–19. doi:10.1523/JNEUROSCI.0498-14.2014. PMC 4205560. PMID 25339752.
- ^ Meyers, Jason R.; Hu, Lily; Moses, Ariel; Kaboli, Kavon; Papandrea, Annemarie; Raymond, Pamela A. (2012). "β-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina". Neural Development. 7: 30. doi:10.1186/1749-8104-7-30. PMC 3549768. PMID 22920725.
- ^ Montgomery, JE; Parsons, MJ; Hyde, DR (2010). "A novel model of retinal ablation demonstrates that the extent of rod cell death regulates the origin of the regenerated zebrafish rod photoreceptors". J Comp Neurol. 518 (6): 800–14. doi:10.1002/cne.22243. PMC 3656417. PMID 20058308.
- ^ Goldman, Daniel (2014). "Müller glial cell reprogramming and retina regeneration -". Nature Reviews Neuroscience. 15 (7): 431–442. doi:10.1038/nrn3723. PMC 4249724. PMID 24894585.
- ^ Webster, Mark K.; Cooley-Themm, Cynthia A.; Barnett, Joseph D.; Bach, Harrison B.; Vainner, Jessica M.; Webster, Sarah E.; Linn, Cindy L. (2017-03-27). "Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist". Neuroscience. 346: 437–446. doi:10.1016/j.neuroscience.2017.01.029. ISSN 1873-7544. PMC 5341387. PMID 28147247.
- ^ "FDA approves first retinal implant for rare eye disease". Reuters. 14 February 2013.
This page was last edited on 3 December 2023, at 13:29