Grant: Project Grant

Humans exhibit a poor ability to regenerate photoreceptors in response to injury or disease. In contrast, other animals, like zebrafish, are capable of regenerating photoreceptors. The regenerative response in zebrafish is mediated by Müller glial cells, which are normally quiescent cells (i.e., they do not divide) and are thought to acquire stem cell characteristics by reprogramming their genome in a process called dedifferentiation in order to replace the lost photoreceptors and ultimately restore vision. However, not all Müller cells participate in the regenerative response and those that do have very limited cell division, and this is presumably to control the numbers of new cells that are produced. In general, the behaviour of Müller cells during dedifferentiation in zebrafish, arguably the best model system to study retinal regeneration, is poorly understood. We aim to capitalize on the natural regenerative ability of Müller cells in zebrafish in order to gain insight into how dedifferentiation is regulated. Specifically, we aim to: (1) Test if genes related to wound repair affect Müller cell shape changes and function in response to a lesion; and (2) Characterize the role of gene networks that control how Müller cells make the decision to divide. Although some regenerative properties are evident in human Müller cells, these cells do not produce new photoreceptors in vivo. Our research will allow us to discover new methods for overcoming the barriers to human Müller cell reprogramming into an active stem cell state. In the long term, this could facilitate the development of new pre-clinical models of human retinal regeneration and bring us closer to an endogenous repair strategy for treating blindness.