Regeneration of the retina
Why does a person's retina not recover?
Biologist Alexey Yerdyakov on retinal stem cells, Muller cells and the ability to regenerate the retina in different organisms
One of the important and interesting questions in the field of pathophysiology of vision is why in some animals the ability to regenerate the retina after its injury has been preserved, but in humans this ability is absent? The ability to regenerate the retina, that is, to its full functional restoration, has long been studied on various animal species, such as zebrafish, spur frogs and newts. After damage, the retina of these animals is completely restored both structurally and functionally. And if a person has an inflammatory process in the retina, it usually ends with the processes of gliosis, that is, proliferation and fibrosis of glial tissue.
One of the important and interesting questions in the field of pathophysiology of vision is why in some animals the ability to regenerate the retina after its injury has been preserved, but in humans this ability is absent? The ability to regenerate the retina, that is, to its full functional restoration, has long been studied on various animal species: zebrafish, spur frogs and newts. After damage, the retina of these animals is completely restored both structurally and functionally. And if a person has an inflammatory process in the retina, it usually ends with the processes of gliosis, that is, proliferation and fibrosis of glial tissue.
Not so long ago, the results of experiments conducted on mice were published. There is a special proneuronal transcription factor, which in mice, mammals and humans is normally in a silent state, that is, inactive. And in danio-rerio fish, it is in an active state, when the retina is damaged, it allows Muller cells to dedifferentiate, give almost all possible types of retinal neurons: photoreceptors, bipolar cells, amacrine cells that process primary visual information at the retinal level.
This proneuronal transcription factor in Muller cells was activated when the retina was artificially injured in mice and damage was introduced. Muller cells underwent dedifferentiation and formed pools of functionally active neurons in the retina. Unfortunately, it was not possible to completely restore the retina, and Muller cells gave exclusively bipolar cells. They no longer produced any other types of neurons as a result of their dedifferentiation.
The question arises: what else can affect the regenerative potential of the retina in mammals? It's not just one transcription factor, although these regulatory mechanisms at the cell level are now being actively studied and many researchers are doing this. It is impossible to say that we can talk about some separate, individual transcription factors. The retina is a complex tissue, we are talking about a large number of different regulatory factors both at the cellular level and at the tissue level. This is a very large, complex system. It needs to be studied comprehensively, not to focus only on the genetic apparatus of the cell and its transcription factors.
But, as happens in biology, information accumulates gradually, so a single concept can mature later. In 10-15 years, we will learn more about transcription factors and macrofactors that regulate inflammatory processes already at the tissue level. Let's understand how it all works together and how we can make the Muller cells regenerate in humans.
Why did it happen in the course of evolution that some organisms retained the ability to regenerate the retina, and some organisms lost it? Currently, the concept is being considered, which consists in the fact that there are two approaches to the restoration of the retina. The first concept is regenerative, when the retina is fully functionally restored from stem cells and from retinal stem cell analogues. This is also called non-proliferative gliosis, that is, glial cells, to which Muller cells also belong, are activated against the background of the development of a local inflammatory reaction. But this activation of glial cells leads to the dedifferentiation of Muller cells and to the fact that the retina of these Muller cells can be restored.
But in humans and mammals, evolution has taken a different path, and a neuroprotection strategy is being implemented. It is good in the short term, that is, tactically it is a good strategy, but strategically it is unsuccessful. This strategy is called proliferative gliosis. With its help, the replacement of functional neurons that process visual information in the retina with glial tissue is realized – this is called gliosis. That is, glia proliferates, and a glious scar is formed, which replaces the area of dead neurons. This strategy is implemented not only for the retina, but for the entire nervous tissue and the brain as well.
In addition to gliosis, fibrous cell membranes form above the retina, under the retina or inside the retina. Replacement occurs not only by glial cells, but also by connective tissue. If we consider regulatory processes, a large number of neurotrophic factors are produced. This is, for example, brain neurotrophic factor BDNF, nerve growth factor NGF. These are different neurotrophins – the third and fourth. Due to the effects of neurotrophic factors, our neurons can survive for a while as long as possible. They ensure the safety of neurons for a short period of time. However, in the future everything ends with the development of total gliosis – the replacement of glial cells and the formation of connective tissue membranes. This strategy is implemented in humans.
In the future, understanding these processes and building a more complete pathophysiological concept of what happens against the background of the development of intraocular inflammation in retinal injuries and comparing these data with what happens in classical organisms on which the regenerative capabilities of the retina are studied will allow us to come to the conclusion that our potentially retinal stem cells regenerate, and from with them, the retina would be restored not only structurally, but also functionally.
About the author:
Alexey Yerdyakov – Candidate of Biological Sciences, Lomonosov Moscow State University, Faculty of Fundamental Medicine.
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