Role of Myo/Nog Cells in Neuroprotection: Evidence from the Light Damaged Retina

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Abstract

Purpose

To identify Myo/Nog cells in the adult retina and test their role in protecting retinal photoreceptors from light damage.

Methods

Light damage was induced by exposing albino rats raised in dim cyclic light to 1000 lux light for 24 hours. In one group of rats, Myo/Nog cells were purified from rat brain tissue by magnetic cell sorting following binding of the G8 monoclonal antibody (mAb). These cells were injected into the vitreous humour of the eye within 2 hours following bright light exposure. Retinal function was assessed using full-field, flash electroretinogram (ERG) before and after treatment. The numbers of Myo/Nog cells, apoptotic photoreceptors, and the expression of glial fibrillary acidic protein (GFAP) in Muller cells were assessed by immunohistochemistry.

Results

Myo/Nog cells were present in the undamaged retina in low numbers. Light induced damage increased their numbers, particularly in the choroid, ganglion cell layer and outer plexiform layer. Intravitreal injection of G8-positive (G8+) cells harvested from brain mitigated all the effects of light damage examined, i.e. loss of retinal function (ERG), death of photoreceptors and the stress-induced expression of GFAP in Muller cells. Some of the transplanted G8+ cells were integrated into the retina from the vitreous.

Conclusions

Myo/Nog cells are a subpopulation of cells that are present in the adult retina. They increase in number in response to light induced stress. Intravitreal injection of Myo/Nog cells was protective to the retina, in part, by reducing retinal stress as measured by the Muller cell response. These results suggest that Myo/Nog cells, or the factors they produce, are neuroprotective and may be therapeutic in neurodegenerative retinal diseases.

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Most cited references 33

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Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration.

Andreas Wenzel, Christian Grimm, Marijana Samardzija … (2005)

Human retinal dystrophies and degenerations and light-induced retinal degenerations in animal models are sharing an important feature: visual cell death by apoptosis. Studying apoptosis may thus provide an important handle to understand mechanisms of cell death and to develop potential rescue strategies for blinding retinal diseases. Apoptosis is the regulated elimination of individual cells and constitutes an almost universal principle in developmental histogenesis and organogenesis and in the maintenance of tissue homeostasis in mature organs. Here we present an overview on molecular and cellular mechanisms of apoptosis and summarize recent developments. The classical concept of apoptosis being initiated and executed by endopeptidases that cleave proteins at aspartate residues (Caspases) can no longer be held in its strict sense. There is an increasing number of caspase-independent pathways, involving apoptosis inducing factor, endonuclease G, poly-(ADP-ribose) polymerase-1, proteasomes, lysosomes and others. Similarly, a considerable number and diversity of pro-apoptotic stimuli is being explored. We focus on apoptosis pathways in our model: light-damage induced by short exposures to bright white light and highlight those essential conditions known so far in the apoptotic death cascade. In our model, the visual pigment rhodopsin is the essential mediator of the initial death signal. The rate of rhodopsin regeneration defines damage threshold in different strains of mice. This rate depends on the level of the pigment epithelial protein RPE65, which in turn depends on the amino acid (leucine or methionine) encoded at position 450. Activation of the pro-apoptotic transcription factor AP-1 constitutes an essential death signal. Inhibition of rhodopsin regeneration as well as suppression of AP-1 confers complete protection in our system. Furthermore, we describe observations in other light-damage systems as well as characteristics of animal models for RP with particular emphasis on rescue strategies. There is a vast array of different neuroprotective cytokines that are applied in light-damage and RP animal models and show diverging efficacy. Some cytokines protect against light damage as well as against RP in animal models. At present, the mechanisms of neuroprotective/anti-apoptotic action represent a "black box" which needs to be explored. Even though acute light damage and RP animal models show different characteristics in many respects, we hope to gain insights into apoptotic mechanisms for both conditions by studying light damage and comparing results with those obtained in animal models. In our view, future directions may include the investigation of different apoptotic pathways in light damage (and inherited animal models). Emphasis should also be placed on mechanisms of removal of dead cells in apoptosis, which appears to be more important than initially recognized. In this context, a stimulating concept concerns age-related macular degeneration, where an insufficiency of macrophages removing debris that results from cell death and photoreceptor turnover might be an important pathogenetic event. In acute light damage, the appearance of macrophages as well as phagocytosis by the retinal pigment epithelium are a consistent and conspicuous feature, which lends itself to the study of removal of cellular debris in apoptosis. We are aware of the many excellent reviews and the earlier work paving the way to our current knowledge and understanding of retinal degeneration, photoreceptor apoptosis and neuroprotection. However, we limited this review mainly to work published in the last 7-8 years and we apologize to all the researchers which have contributed to the field but are not cited here.

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The susceptibility of the retina to photochemical damage from visible light.

Jennifer J. Hunter, Jessica I.W. Morgan, William H. Merigan … (2012)

The photoreceptor/RPE complex must maintain a delicate balance between maximizing the absorption of photons for vision and retinal image quality while simultaneously minimizing the risk of photodamage when exposed to bright light. We review the recent discovery of two new effects of light exposure on the photoreceptor/RPE complex in the context of current thinking about the causes of retinal phototoxicity. These effects are autofluorescence photobleaching in which exposure to bright light reduces lipofuscin autofluorescence and, at higher light levels, RPE disruption in which the pattern of autofluorescence is permanently altered following light exposure. Both effects occur following exposure to visible light at irradiances that were previously thought to be safe. Photopigment, retinoids involved in the visual cycle, and bisretinoids in lipofuscin have been implicated as possible photosensitizers for photochemical damage. The mechanism of RPE disruption may follow either of these paths. On the other hand, autofluorescence photobleaching is likely an indicator of photooxidation of lipofuscin. The permanent changes inherent in RPE disruption might require modification of the light safety standards. AF photobleaching recovers after several hours although the mechanisms by which this occurs are not yet clear. Understanding the mechanisms of phototoxicity is all the more important given the potential for increased susceptibility in the presence of ocular diseases that affect either the visual cycle and/or lipofuscin accumulation. In addition, knowledge of photochemical mechanisms can improve our understanding of some disease processes that may be influenced by light exposure, such as some forms of Leber's congenital amaurosis, and aid in the development of new therapies. Such treatment prior to intentional light exposures, as in ophthalmic examinations or surgeries, could provide an effective preventative strategy. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Mechanisms of photoreceptor death and survival in mammalian retina.

J. Stone (1999)

The mammalian retina, like the rest of the central nervous system, is highly stable and can maintain its structure and function for the full life of the individual, in humans for many decades. Photoreceptor dystrophies are instances of retinal instability. Many are precipitated by genetic mutations and scores of photoreceptor-lethal mutations have now been identified at the codon level. This review explores the factors which make the photoreceptor more vulnerable to small mutations of its proteins than any other cell of the body, and more vulnerable to environmental factors than any other retinal neurone. These factors include the highly specialised structure and function of the photoreceptors, their high appetite for energy, their self-protective mechanisms and the architecture of their energy supply from the choroidal circulation. Particularly important are the properties of the choroidal circulation, especially its fast flow of near-arterial blood and its inability to autoregulate. Mechanisms which make the retina stable and unstable are then reviewed in three different models of retinal degeneration, retinal detachment, photoreceptor dystrophy and light damage. A two stage model of the genesis of photoreceptor dystrophies is proposed, comprising an initial "depletion" stage caused by genetic or environmental insult and a second "late" stage during which oxygen toxicity damages and eventually destroys any photoreceptors which survive the initial depletion. It is a feature of the model that the second "late" stage of retinal dystrophies is driven by oxygen toxicity. The implications of these ideas for therapy of retinal dystrophies are discussed.

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Author and article information

Contributors

Demetrios G. Vavvas: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 18 January 2017

Publication date Collection: 2017

Volume: 12

Issue: 1

Electronic Location Identifier: e0169744

Affiliations

[1 ]Bosch Institute and Discipline of Physiology, University of Sydney, Sydney, Australia

[2 ]Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United States of America

[3 ]Lankenau Institute for Medical Research, Wynnewood, PA, United States of America

Massachusetts Eye & Ear Infirmary, Harvard Medical School, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceptualization: ABN AB MGW JS.
Data curation: ABN AB.
Formal analysis: ABN AB.
Funding acquisition: JS MGW.
Investigation: ABN AB JG MGW SP CS.
Methodology: ABN AB JG MGW SP CS.
Project administration: ABN AB JG MGW SP CS.
Resources: ABN AB JG MGW SP CS.
Supervision: ABN JS MGW.
Validation: ABN AB JG MGW SP CS.
Visualization: ABN AB JG MGW SP CS.
Writing – original draft: ABN AB JG MGW.
Writing – review & editing: ABN AB JG MGW SP CS.

* E-mail: Dr.Arturo.Bravo@ 123456gmail.com

Article

Publisher ID: PONE-D-16-16928

DOI: 10.1371/journal.pone.0169744

PMC ID: 5242434

PubMed ID: 28099524

SO-VID: b87bf802-de26-47be-b5e4-dc08ba918b3f

License:

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.

History

Date received : 26 April 2016

Date accepted : 21 December 2016

Page count

Figures: 6, Tables: 0, Pages: 15

Funding

Funded by: Supported by the Sir Zelman Cowen Universities Fund

Award Recipient : Jonathan Stone

Supported by the Sir Zelman Cowen Universities Fund and Institutional Funding to ABN by the Lankenau Institute for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All data files are available from the Figshare database and are accessible by the following URL: https://figshare.com/articles/Data_for_figures_2_to_6_xlsx/4256576.

Role of Myo/Nog Cells in Neuroprotection: Evidence from the Light Damaged Retina

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Abstract

Purpose

Methods

Results

Conclusions

Related collections

PLOS Climate

Most cited references 33

Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration.

The susceptibility of the retina to photochemical damage from visible light.

Mechanisms of photoreceptor death and survival in mammalian retina.

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