Retinal regeneration

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Rods, cones and nerve layers in the retina. The front (anterior) of the eye is on the left. Light (from the left) passes through several transparent nerve layers to reach the rods and cones (far right). A chemical change in the rods and cones send a signal back to the nerves. The signal goes first to the bipolar and horizontal cells (yellow layer), then to the amacrine cells and ganglion cells (purple layer), then to the optic nerve fibres. The signals are processed in these layers. First, the signals start as raw outputs of points in the rod and cone cells. Then the nerve layers identify simple shapes, such as bright points surrounded by dark points, edges, and movement. (Based on a drawing by Ramon y Cajal.) Retina-diagram.svg
Rods, cones and nerve layers in the retina. The front (anterior) of the eye is on the left. Light (from the left) passes through several transparent nerve layers to reach the rods and cones (far right). A chemical change in the rods and cones send a signal back to the nerves. The signal goes first to the bipolar and horizontal cells (yellow layer), then to the amacrine cells and ganglion cells (purple layer), then to the optic nerve fibres. The signals are processed in these layers. First, the signals start as raw outputs of points in the rod and cone cells. Then the nerve layers identify simple shapes, such as bright points surrounded by dark points, edges, and movement. (Based on a drawing by Ramón y Cajal.)

Retinal regeneration refers to the restoration of vision in vertebrates that have suffered retinal lesions or retinal degeneration.

Contents

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.

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]

ProteinGeneral RoleRole in Retinal Regeneration
TNF-a induces inflammation, induces apoptosis signals Muller glia to dedifferentiate
Notch regulates differentiation and cell fate determinationmaintains Muller glial quiescence
N-cadherin mediates cell-cell interactions, stimulates axonal guidance guides neural progenitor cell migration
Ascl1 mediates neurogenesiscontributes to Muller glial dedifferentiation
β-catenin actives the Wnt pathwaynecessary 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

Section through retina Gray881.png
Section through retina

In February 2013, the US Food and Drug Administration approved the use of the Argus II Retinal Prosthesis System , [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.

Related Research Articles

<span class="mw-page-title-main">Retina</span> Part of the eye

The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Photoreceptor cell</span> Type of neuroepithelial cell

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

<span class="mw-page-title-main">Glia</span> Support cells in the nervous system

Glia, also called glial cells(gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. The neuroglia make up more than one half the volume of neural tissue in our body. They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells and microglia, and in the peripheral nervous system they include Schwann cells and satellite cells.

<span class="mw-page-title-main">Retinal ganglion cell</span> Type of cell within the eye

A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.

<span class="mw-page-title-main">Retina bipolar cell</span> Type of neuron

As a part of the retina, bipolar cells exist between photoreceptors and ganglion cells. They act, directly or indirectly, to transmit signals from the photoreceptors to the ganglion cells.

<span class="mw-page-title-main">Melanopsin</span> Mammalian protein found in Homo sapiens

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. They are typically identified in the human by co-expression of PDGFRA and CSPG4.

Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence of ipRGCs was first suspected in 1927 when rodless, coneless mice still responded to a light stimulus through pupil constriction, This implied that rods and cones are not the only light-sensitive neurons in the retina. Yet research on these cells did not advance until the 1980s. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light-sensitive protein. Therefore, they constitute a third class of photoreceptors, in addition to rod and cone cells.

Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

Thomas A. Reh is an American scientist and author.

Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.

<span class="mw-page-title-main">Radial glial cell</span> Bipolar-shaped progenitor cells of all neurons in the cerebral cortex and some glia

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.

<span class="mw-page-title-main">Müller glia</span> Glial cell type in the retina

Müller glia, or Müller cells, are a type of retinal glial cells, first recognized and described by Heinrich Müller. They are found in the vertebrate retina, where they serve as support cells for the neurons, as all glial cells do. They are the most common type of glial cell found in the retina. While their cell bodies are located in the inner nuclear layer of the retina, they span across the entire retina.

Neurogenins, often abbreviated as Ngn, are a family of bHLH transcription factors involved in specifying neuronal differentiation. The family consisting of Neurogenin-1, Neurogenin-2, and Neurogenin-3, plays a fundamental role in specifying neural precursor cells and regulating the differentiation of neurons during embryonic development. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.

Endogenous regeneration in the brain is the ability of cells to engage in the repair and regeneration process. While the brain has a limited capacity for regeneration, endogenous neural stem cells, as well as numerous pro-regenerative molecules, can participate in replacing and repairing damaged or diseased neurons and glial cells. Another benefit that can be achieved by using endogenous regeneration could be avoiding an immune response from the host.

<span class="mw-page-title-main">Retinal precursor cells</span> Type of cell in the human eye

Retinal precursor cells are biological cells that differentiate into the various cell types of the retina during development. In the vertebrate, these retinal cells differentiate into seven cell types, including retinal ganglion cells, amacrine cells, bipolar cells, horizontal cells, rod photoreceptors, cone photoreceptors, and Müller glia cells. During embryogenesis, retinal cells originate from the anterior portion of the neural plate termed the eye field. Eye field cells with a retinal fate express several transcription factor markers including Rx1, Pax6, and Lhx2. The eye field gives rise to the optic vesicle and then to the optic cup. The retina is generated from the precursor cells within the inner layer of the optic cup, as opposed to the retinal pigment epithelium that originate from the outer layer of the optic cup. In general, the developing retina is organized so that the least-committed precursor cells are located in the periphery of the retina, while the committed cells are located in the center of the retina. The differentiation of retinal precursor cells into the mature cell types found in the retina is coordinated in time and space by factors within the cell as well as factors in the environment of the cell. One example of an intrinsic regulator of this process is the transcription factor Ath5. Ath5 expression in retinal progenitor cells biases their differentiation into a retinal ganglion cell fate. An example of an environmental factor is the morphogen sonic hedge hog (Shh). Shh has been shown to repress the differentiation of precursor cells into retinal ganglion cells.

Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). In short, it is brain growth in relation to its organization. This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.

Jane Caroline Sowden is a British biologist who is Professor of Developmental Biology and Genetics at the Great Ormond Street Hospital for Children NHS Foundation Trust. Her research investigates eye formation and repair by developing a better understanding the genetic pathways that regulate eye development.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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)
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ "FDA approves first retinal implant for rare eye disease". Reuters. 14 February 2013.
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