Fight Aging!

In situ cell reprogramming is an interesting approach to the treatment of degenerative blindness conditions in which photoreceptor cells are lost, but the retinal structure is otherwise largely intact. A number of demonstrations have been carried out in the past five years, in cell cultures and in mice. Here is the latest example of this line of work, in which preliminary evidence indicates that some degree of vision is restored. It is of course not all that easy to determine the quality of vision obtained in mice though any successful therapy for blindness; light sensitivity is one thing, but what exactly do they see in this scenario? Those quantifying efforts still lie ahead.

In vertebrates, Müller glia cells are the most common type of non-neuronal cells found in the retina and provide structural and functional stability for photoreceptor rods and cones. In cold-blooded vertebrates, such as zebrafish, Müller glia act as retinal stem cells, multiplying after retinal injury and reprogramming themselves as photoreceptor cells to replace damaged ones. In mammals, however, Müller glia cells do not spontaneously reprogram themselves into stem cells and then photoreceptor cells to replace damaged ones after injury.

Based on the data in zebrafish and other nonmammalian species, researchers have been looking for the correct cocktail of gene products to coax Müller glia to revert to a stem-cell-like state and then differentiate into retinal cells in mammals. In this study, researchers reprogrammed Müller glia cells into rod photoreceptors in the retinas of uninjured mice, both in wildtype mice and in two strains that serve as models of congenital blindness. The team developed a two-step technique, first injecting an adeno-associated virus with a gene that expresses β-catenin, a protein that helps the glia re-enter the cell cycle, into the retinas of the four-week-old mice. Two weeks later, the mice received a second injection of an adeno-associated virus with the genes that express the transcription factors Otx2, Crx, and Nrl - shown in past studies to aid in the development of rod photoreceptors.

After the second injection, when Müller glia divided, one daughter cell became a rod photoreceptor while the other remained a Müller glia cell. The new rods produced proteins characteristic of the light-sensing retinal cells. Recording light responses from retinal ganglion cells in the retinas of mutant mice that got the gene therapy showed that some of the cells responded, whereas none of the cells responded in mutant mice that did not receive the treatment. The team also detected light responses in the primary visual cortex of the brains of the treated mutant mice but not in the same brain region of untreated blind mice.

Link: https://www.the-scientist.com/news-opinion/reprogrammed-mu-ller-glia-restore-vision-in-mice-64644