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Y. J. Liao, Y.-W. Chen, J. Weimann, L. Recht; Transplantation of Differentiated Embryonic Stem Cells for Re-Population of Retinal Ganglion Cells in the Adult. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3144.
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The mammalian central nervous system has limited regenerative abilities. As a result, injury and disease typically lead to irreversible neuronal loss and permanent functional impact. Stem cell transplantation, despite being in its infancy, promises the greatest potential for re-population and re-engineering of neural circuit. Embryonic stem (ES) cells are totipotent cells that can undergo unlimited self-renewal and differentiate into any adult cell type. We have previously injected differentiated ES cells into the visual cortex, which led to prominent axon projections to the dorsal superior colliculus, which is important for pupillary response and visually guided behavior. Next, we tackled regenerative therapy to replenish retinal ganglion cells.
We grew enhanced green fluorescent protein-positive ES cells on a confluent layer of MS5 cells. After 6 days of co-culture, we generated colonies of neural precursor cells, with few cells expressing Oct3/4 (an ES cell marker), 80% expressing nestin (proliferative marker), and 30% expressing class-III beta-tubulin, an early marker for retinal ganglion cells. We transplanted differentiated ES cells into adult wild-type mice and performed morphometric analyses.
We found that compared to subretinal injection, intravitreal injection was technically easier and led to superior transplantation efficacy. Transplantation was also enhanced by induction of retinal fate by treating ES cells at days 1 and 3 with noggin, a BMP inhibitor, and dkk1, a Wnt inhibitor. Lastly, retina lasering, a technique already well established in humans for treatment of diabetic retinopathy and other diseases, dramatically enhanced stem cell survival and caused elaboration of neurite-like processes which extended over 800-microns from the peripheral retina to the optic nerve head.
Regenerative therapy using embryonic stem cells is feasible in adult mammals. Different techniques, including intravitreal injection of retinal progenitors and retina lasering provide a permissive environment for robust stem cell survival and extension of processes.
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