Directed transdifferentiation of Muller glial cells to photoreceptors using the sonic hedgehog signaling pathway agonist purmorphamine

Specification of distinct cell types from Muller glial cells is key to the potential application of endogenous repair in retinal regeneration. Sonic hedgehog (SHH) has been established as a potent mitogen for rat Muller glial cells, which also induces Muller glial cells to dedifferentiate and adopt the phenotype of rod photoreceptors. The present study investigated the effects of purmorphamine, a small molecule that activates the SHH-pathway, in the proliferation, dedifferentiation and transdifferentiation of Muller glial cells, as determined by several methods including immunofluorescence, polymerase chain reaction and western blotting. It was demonstrated that it may be able to replace SHH for the regeneration of retinal neurons. Purmorphamine was revealed to stimulate the proliferation of Muller glial cells by increasing the expression of cyclin D1 and cyclin D3. In addition, purmorphamine-treated Muller glial cells were induced to dedifferentiate by inducing the expression of progenitor-specific markers; subsequently differentiating into rod-like photoreceptors. Intraocular injection of purmorphamine promoted the activation of Muller glial cells, and in turn, the production of rod-like photoreceptors in acute damaged retina. These results suggested that the endogenous neurogenic capacity of retinal Muller glial cells may be enhanced by this small molecular agonist of the SHH signaling pathway.