When the retina’s light sensory cells in the eye are destroyed, they no longer grow back. This is why diseases such as age-related macular degeneration (AMD) often lead to blindness. But now an experiment by US researchers is raising hope: They have been able to convert skin cells from humans and mice directly and in a relatively short time into rods – the photoreceptors of the retina that are important for light-dark perception. A transplant of these cells into the retina of blind mice gave eyesight back to almost half of the animals: they could again differentiate between light and dark.
In retinal diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa, the light-sensitive cells of the outer retinal layer gradually and perish. As a result, vision continues to decrease until the patient finally loses their eyesight. Untreated diabetes can also destroy the retinal photoreceptors over time. In contrast to many other cells and tissues in our body, the photoreceptors of the retina cannot regenerate, they do not grow back on their own. In order to still show eyesight to those affected, one would have to replace the rods and cones with technical or organic sensory cells. There are already initial tests with chips implanted in the retina, but experiments are also being carried out with stem cells. To do this, scientists first put differentiated body cells back into the state of stem cells and then cause them to develop into light-sensory cells.
Skin cells become chopsticks
However, obtaining replacement retinal cells from stem cells is extremely time-consuming and complicated. The entire process of reprogramming can take six months to get the cells you want for a retinal transplant. “This makes these methods a challenge for practical use in clinical therapy,” explain Biraj Mahato from the University of North Texas and his colleagues. They were therefore looking for a method to convert adult connective tissue cells of the skin, so-called fibroblasts, directly into photoreceptor cells without the detour via stem cells. The starting point was a combination of four chemical compounds with which researchers had previously made fibroblasts into neurons. The tests by Mahato and his team showed that it is possible to use these four chemicals in combination with a fifth substance to reprogram fibroblasts into rod-like light-sensory cells.
“This is the first study that shows that photoreceptor-like cells can be produced by direct chemical reprogramming,” says co-author Anand Swaroop of the US National Eye Institute in Bethesda. Additional analyzes showed that the gene activity of these converted cells was similar to that of normal light-sensory cells: genes typical of rods were read, while genes typical of fibroblasts were down-regulated. The researchers succeeded in direct conversion with both fibroblast cells in mice and with human connective tissue cells, as they report. The entire process to the finished photoreceptor only took around ten days.
Treated mice react to light again
The crucial question, however, is whether these light sensory cells produced in the Petri dish also grow and function in the retina. To test this, the scientists transplanted their newly grown cells into the retina of 14 mice, which are blind when certain genes are switched off and have no functional photoreceptors in their retina. The result: “Six of the 14 mice showed a pupil reflex three to four weeks after the transplant even in low light,” report Mahato and his colleagues. This involuntary contraction of the pupil when light is incident only occurs when the rods in the retina are functioning. In a further experiment, the researchers tested whether the mice demonstrated their preference for darker cage areas, which is typical for them. In fact, the six animals, which had previously shown the pupil reflex, avoided the brighter areas in the experimental enclosure. In contrast, this was not the case with untreated control animals.
“These results provide evidence that chemically induced photoreceptor cells can restore the visual function of blind mice,” say the scientists. Closer examination revealed that the implanted cells in the six sighted mice had grown in the retina and that nerve connections to them had also formed. Even three months after the transplant, these new photoreceptors were still intact and active, as Mahato and his colleagues report. In contrast, in the eight animals in which the treatment had not worked, there were hardly any transplanted cells in the retina. According to the researchers, this suggests that their method is fundamentally suitable for producing functional replacement cells for the retina.
However, the success rate for the transplantation is still too low and the density of the grown cells is not sufficient to restore full vision – so far the mice have only been able to distinguish between light and dark. It will therefore take some time before this or a similar process can also be used in humans. Nevertheless, the scientists see their approach as a promising method to replace destroyed photoreceptors in the future. “It is also important that we found out how this direct reprogramming works at the cellular level,” explains Swaroop. “These findings could help to generate not only replacement cells for the retina, but also many other cell types.”
Source: Biraj Mahato (University of North Texas, Fort Worth) et al., Nature, doi: 10.1038 / s41586-020-2201-4