Some highly regenerative species, such as zebrafish, are capable of repairing nervous system tissue such as the retina. As in all investigations of the comparative biology of regeneration, the question remains as to whether or not these underlying mechanisms of adult regeneration also exist in mammals, turned off beneath a layer of suppressive regulation. If so, then perhaps there is a comparatively simple path towards regrowth of injury and, possibly, repair of age-related damage. It seems the field is still some way distant from a definitive answer as to whether or not this is the case, however, and we should probably not expect anything in cellular biochemistry to turn out to be simple at the end of the day. Still, progress is being made, as illustrated here.
Although the mammalian retina does not spontaneously regenerate, researchers have now found that it has a regenerative capacity that is kept dormant by a cellular mechanism called the Hippo pathway. The discovery opens the possibility of activating the retina's ability to restore lost vision by manipulating this pathway. Damage to the retina can lead to irreparable loss of vision in humans and other mammals because their retinas do not regenerate. However, other animals such as zebrafish can reverse blindness thanks to specialized cells in the retina called Müller glial cells. When the retina is damaged, Müller glial cells proliferate and differentiate into the lost retinal neurons, effectively replacing injured cells with fully functional ones.
Although Müller glial cells in injured mammalian retina do not restore vision as their counterpart in zebrafish do, other researchers have shown that, when the mammalian retina is injured, a small subset of Müller glial cells takes the first steps needed to enter the proliferation cycle, such as acquiring molecular markers scientists expect to see in a proliferating cell. This attempt to proliferate is transient; after acquiring some of the cell markers the cells shut off. These observations suggested that the mechanism that drives cell repair in zebrafish also might be present in mammals, but it is actively suppressed.
Searching for the proposed suppressing mechanism, researchers focused their attention on the Hippo pathway, a network of molecular events that contributes to organ growth during development and to the regulation of heart tissue regeneration in response to myocardial infarction. The researchers first determined that the Hippo pathway is expressed in mammalian Müller glial cells. Then, they investigated whether altering the Hippo pathway in these cells would affect their ability to proliferate. Creating a malfunctioning Hippo pathway by eliminating two of its molecular steps resulted in modest cell proliferation. And when the researchers genetically engineered Müller glial cells to carry a version of YAP that is impervious to the inhibitory influence of Hippo, the cells showed major proliferation and acquired a progenitor cell identity. Importantly, a small subset of these Müller glia-derived progenitor cells showed signs of spontaneous differentiation into new retinal neurons. "Our next step is to develop a strategy to guide proliferating Müller glial cells into differentiation pathways leading to retinal cells capable of restoring vision."