Zebrafish can repair retinal damage and restore lost vision, so why can’t we? In zebrafish, specialized retinal cells called Müller glial cells (MGs) can see their way through a regenerative pathway, one that allows them to undergo cellular reprogramming and to reach a proliferative, progenitor state. MGs also exist in humans and other mammals. After retinal injury, some of these MGs start groping their way toward regeneration, but then something gets in the way.

This something, reported scientists based at the Baylor College of Medicine, is the Hippo mechanism, 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. According to the Baylor scientists, who were led by Ross A. Poché, PhD, and James Martin, MD, PhD, Hippo is expressed in mammalian MGs, where it represses a transcription factor and keeps MGs from activating their latent regenerative capacity.

Poché pointed out that when mammals suffer retinal damage, a small subset of MGs takes the first steps needed to enter the proliferation cycle, such as acquiring molecular markers scientists expect to see in a proliferating cell. “But this attempt to proliferate is transient. After acquiring some of the cell markers the cells shut off,” said Poché. “These observations suggested that the mechanism that drives cell repair in zebrafish also might be present in mammals, but it is actively suppressed. For years, the suppressing mechanism was unknown.”

To identify the suppressing mechanism, the Poché lab combined forces with the Martin lab, which had previously shown that Hippo dampens cardiomyocyte proliferation by inhibiting the activity of another pathway called YAP. Working together, the Poché and Martin labs explored whether altering Hippos in mammalian MGs would affect their ability to proliferate.

The results of this work appeared May 7 in the journal Cell Reports, in an article titled, “The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming.” This article describes how the researchers created a malfunctioning Hippo pathway by eliminating two of its molecular steps. It also details how the researchers genetically engineered MGs to carry a version of YAP called YAP5SA that is impervious to the inhibitory influence of Hippo.

“MG-specific deletion of Hippo pathway components Lats1 and Lats2, as well as transgenic expression of a Hippo non-responsive form of YAP (YAP5SA), resulted in dramatic Cyclin D1 upregulation, loss of adult MG identity, and attainment of a highly proliferative, progenitor-like cellular state,” the article’s authors wrote. “Our results reveal that mammalian MGs may have latent regenerative capacity that can be stimulated by repressing Hippo signaling.”

In mammals, Hippo signaling prevents Müller glial reprogramming to a proliferative, progenitor-like state. Repressing Hippo could restore latent regenerative capacity. [Cell Reports]

Importantly, the researchers observed that a small subset of the progenitor cells derived from MGs showed signs of spontaneous differentiation into new retinal neurons.

“Up to this point researchers did not know what endogenous blocking mechanism prevented MGs from entering a regenerative state. The Hippo pathway is a new molecular entry point to that mechanism,” said Poché. “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.”