Japanese researchers from RIKEN and Kyoto University have demonstrated retinal regeneration in a
mammalian model of retinal degeneration after stimulation of the Wnt signaling pathway, which functions
as a regulator of some adult stem cell populations—in addition to its better known roles in
embryogenesis and development.
It is a discovery that may ultimately lead to new therapies for retinal diseases including the degenerative
disease called retinitis pigmentosa.
Previous research by the team led by Masayo Takahashi at the RIKEN Center for Developmental Biology,
Kobe, demonstrated that retinal support cells called Müller glia could de-differentiate to assume a
neuronal fate, but the level of regeneration via this mechanism was very low, occurring in just a few
cells.
But the new study, published recently in the Journal of Neuroscience (1), indicates that retinal cell
regeneration in an in vitro model of retinal damage can be increased by as much as twenty-fold in the
presence of the protein Wnt3a.
The researchers initially performed experiments in cultured retinas isolated from rats. When they
administered Wnt3a, they found a significant increase in proliferation of neuronal progenitors from the
de-differentiated cells (Fig. 1 - Click on link below).
“Newly generated cells constituted almost a layer of cells in the outer nuclear layer in the retinal
degeneration model mice,” says Takahashi. “We only observed several cells per field without Wnt
treatment. Furthermore, the retinal neurons were regenerated all over the retina.”
The regenerated cells migrated to the outer nuclear layer of the retina, where, in the presence of retinoic
acid (a form of vitamin A) or valproic acid, the team observed differentiation into rod photoreceptor cells.
The phenomenon appears to involve the canonical Wnt signaling pathway, in which Wnt activation
protects the β-catenin protein from degradation, allowing it to accumulate in the nucleus where it
regulates gene transcription. The process could also be stimulated with small molecule inhibitors of
glycogen synthase kinase-3β, which normally blocks activation of the pathway.
Treatment of retinas isolated from a murine model of retinitis pigmentosa with Wnt3a similarly resulted in
the regeneration of retinal cells, suggesting that the Wnt/β-catenin signaling pathway contributes to
central nervous system regeneration. Takahashi believes Wnt signaling may be a part of the natural
restoration mechanism in the retina.
Reference
1. Osakada, F., Ooto, S., Akagi, T., Mandai, M., Akaike, A. & Takahashi, M. Wnt signaling promotes regeneration in the retina of adult mammals. Journal of Neuroscience 27, 4210–4219 (2007).
