Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets

BACKGROUND: Many retinal degenerative diseases are caused by the loss of retinal ganglion cells (RGCs). Autosomal dominant optic atrophy is the most common hereditary optic atrophy disease and is characterized by central vision loss and degeneration of RGCs. Currently, there is no effective treatment for this group of diseases. However, stem cell therapy holds great potential for replacing lost RGCs of patients. Compared with embryonic stem cells, induced pluripotent stem cells (iPSCs) can be derived from adult somatic cells, and they are associated with fewer ethical concerns and are less prone to immune rejection. In addition, patient-derived iPSCs may provide us with a cellular model for studying the pathogenesis and potential therapeutic agents for optic atrophy. METHODS: In this study, iPSCs were obtained from patients carrying an OPA1 mutation (OPA1(+/−)-iPSC) that were diagnosed with optic atrophy. These iPSCs were differentiated into putative RGCs, which were subsequently characterized by using RGC-specific expression markers BRN3a and ISLET-1. RESULTS: Mutant OPA1(+/−)-iPSCs exhibited significantly more apoptosis and were unable to efficiently differentiate into RGCs. However, with the addition of neural induction medium, Noggin, or estrogen, OPA1(+/−)-iPSC differentiation into RGCs was promoted. CONCLUSIONS: Our results suggest that apoptosis mediated by OPA1 mutations plays an important role in the pathogenesis of optic atrophy, and both noggin and β-estrogen may represent potential therapeutic agents for OPA1-related optic atrophy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-015-0264-1) contains supplementary material, which is available to authorized users.