Abstract
Stem cell-based photoreceptor differentiation strategies have been the recent focus of therapies for retinal degenerative diseases. Previous studies utilized embryonic stem (ES) cells and neural retina differentiation cocktails, including DKK1 and Noggin. Here, we show a novel microRNA-mediated strategy of retina differentiation from somatic stem cells, which are potential allogeneic cell sources. Human amniotic epithelial stem cells (AESCs) and umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) treated with a retina differentiation cocktail induced gene expressions of retina development-relevant genes. Furthermore, microRNA-203 (miR-203) is abundantly expressed in human AESCs and human UCB-MSCs. This miR-203 is predicted to target multiple retina development-relevant genes, particularly DKK1, CRX, RORβ, NEUROD1, NRL and THRB. The inhibition of miR-203 induced a retina differentiation of AESCs and UCB-MSCs. Moreover, successive treatments of anti-miR-203 led to the expression of both mature photoreceptor (PR) markers, rhodopsin and opsin. In addition, we determined that CRX, NRL and DKK1 are direct targets of miR-203 using a luciferase assay. Thus, the work presented here suggests that somatic stem cells can potentially differentiate into neural retina cell types when treated with anti-miR-203. They may prove to be a source of both PR subtypes for future allogeneic stem cell-based therapies of non-regenerative retina diseases.
Highlights
Neural retina degeneration is a human eye disorder that leads to the loss of vision due to the decay of various cell types in the neural retina [1]
Other studies have reported that both cone and rod PR cells can be derived from human embryonic stem (ES) and induced pluripotent stem (iPS) cells [4,5,6,7]; mouse ES cell aggregates were shown to form the optic cup www.impactjournals.com/oncotarget structure, which is composed of the neural retina and retinal pigmented epithelial (RPE) [8]
We show that anti-miR-203 treatment can mediate the differentiation of somatic stem cells into neural retina cell types, PR cells
Summary
Neural retina degeneration is a human eye disorder that leads to the loss of vision due to the decay of various cell types in the neural retina [1]. Cone-rod dystrophy is one type of neural retina degenerative disease that causes a depletion of the outer nuclear layer, which consists of cone and rod PR cells. Both types of PRs are involved in visual signal transduction, along with retinal pigmented epithelial (RPE) cells, as confirmed by their response to light. The results revealed that the effective differentiation of neural retina progenitor cells could be promoted by the addition of DKK1 and Noggin In support of these results, both the Wnt and BMP signaling pathways are known to antagonistically influence neural development [9,10,11]
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