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Editors Selection IGR 18-2
Basic Science: Stem cells and Neuroregeneration
Comment by Karl Wahlin on:
70331 Generation of Functional Human Retinal Ganglion Cells with Target Specificity from Pluripotent Stem Cells by Chemically Defined Recapitulation of Developmental Mechanism, Teotia P; Chopra DA; Dravid SM et al., Stem Cells, 2017; 35: 572-585
Glaucoma is a complex group of diseases in which retinal ganglion cell (RGC) loss leads to permanent blindness. Despite years of intense research effort, few effective long-term treatments exist. One promising approach may include stem cells to replace dead/dying RGCs or to study them in a dish to identify pathways that can halt or reverse this degeneration. Work by Teotia et al. moves us one step closer to this goal through their systematic differentiation process allowing one to attain functional RGCs in vitro.
Under the same growth conditions, mouse RGCs readily exhibited robust electrical activity while mouse stem cell-derived RGCs did not
Teotia and colleagues combined decades of basic research in the RGC developmental biology arena and merged this with recent advances in stem cell biology. The end result is a hierarchical protocol utilizing a dozen small molecules and growth factors to optimize early retina development, ganglion cell growth and cell maturity. The retina stem cell field has only recently placed a greater emphasis on cell function. Of interest is, that under the same growth conditions, mouse RGCs readily exhibited robust electrical activity while mouse stem cell-derived RGCs did not.
Upon further investigation, it was identified that the REST pathway, which is known to negatively regulate RGC development, was a key difference here. Indeed, by blocking this pathway, a significant increase in voltage-dependent firing of new RGCs was observed. Human electrical recordings also revealed evidence of activity-dependent firing, suggesting that the three-stage differentiation approach described here was effective across species. By extension, it could also be applicable to human cells from different genetic backgrounds, such as for studying patient specific iPSC derived RGCs. 'Reproducible' methods for generating RGCs across many different genetic backgrounds still needs to be demonstrated. However, the system described here could offer one way to do so and thus brings this field one step closer to the end goal.
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