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Mini retinas develop light-sensitive photoreceptors in the lab

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Review of ‘Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs’ from Nature Communications, by Carla Mellough

For the first time, researchers from John Hopkins University School of Medicine have created 3D retinal tissue containing light-sensitive photoreceptors in the lab using stem cells [1]. The photoreceptor cells of the eye are the first step in the phototransduction cascade; a chain of events which convert light entering the eye into electrical signals, allowing us to see. Many forms of blindness are caused by the disruption of photoreceptor function and, unfortunately, many remain incurable. The transplantation of new, functional photoreceptor cells into the eyes of these patients represents one of the most promising therapeutic avenues towards restoring vision. Great progress in this direction, marked by the ability to generate 3D retinal tissue from human stem cells [2], has however been stunted by the inability of researchers to prove that photoreceptors generated from stem cells can respond to light – the essential activity of photoreceptors for vision to occur. An elegant study recently published in Nature Communications, led by Maria Valeria Canto-Soler, demonstrates what we have been eagerly waiting in this field - the production of light-sensitive photoreceptors from stem cells [1].

By directing human induced pluripotent stem cells (hiPSCs) through a relatively simple differentiation protocol in the lab, first under 2D culture conditions and then in 3D, the authors demonstrate that the resulting retinal tissue which develops is laminated, with each lamina containing different specialized retinal cells in a similar fashion to developing human retina. This ability has been previously demonstrated in the field, however what makes the work by Zhong et al so novel, is that the photoreceptors which develop in their study within the retinal tissue go on to mature to a level that has not yet been seen. Specifically, the hiPSC-derived photoreceptors developed outer segment discs, a specialized feature of photoreceptor cells and the region where phototransduction is known to start and, importantly, they responded to light. The retinal differentiation field uses a common artillery of exogenous signaling factors to direct stem cell fate, although stem cells do have the capability to self-organize into retinal tissue under minimal conditions. Zhong et al used a minimal media approach at the early stages, and attribute their success to the addition of fetal bovine serum and taurine from week 7 through 17, a window of retinoic acid exposure over weeks 10-14, and the prolonged culture period (28 weeks).

These are extremely exciting results for researchers in the field and patients alike. This work has incredible implications not only for transplantation therapy, but also for personalized medicine, the development of new drugs to treat blindness, and may also help scientists to better understand photoreceptor-related disease. There are, however, some points to take into consideration. First, is the very low number of light-sensitive cells that the author’s report – only 2 of the 13 cells chosen for electrophysiological experiments responded to light and the photosensitivity was very low. Secondly, there are two types of photoreceptors in the retina; those which function under low light levels (rods) and those which function under light conditions (cones) and, in this study, predominantly rod photoreceptors were produced. This is great news for patients suffering from rod-associated blindness, but our central vision which allows us to read, write and drive a car relies on the presence of healthy cone photoreceptors. If we can fine-tune this system in order to yield both photoreceptor cell types and encourage a greater number to develop light sensitivity, then the development of new cures for blindness may be even closer than we think.

Related Articles
Human stem cells used to create light-sensitive retina in a dish, Science Daily
Light-sensitive retina created with human stem cells, Medical News Today
Retina Created With Stem Cells in Dish, Guardian Liberty Voice
'Eye-in-a-dish' hope for blindness, RP Fighting Blindness

References
1. Zhong X, Gutierrez C, Xue T, et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 2014;5:4047.
2. Nakano T, Ando S, Takata N, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 2012;10:771-785.