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Alexandra Capela, Laura Fernandez-Sanchez, Trevor McGill, Bin Lu, Raymond Lund, Stephen Huhn, Nicolas Cuenca; Human neural stem cells phagocytose photoreceptor outer segments and preserve synaptic contacts in the degenerating rodent retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2210.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies in our lab have shown that transplantation of human central nervous system stem cells (HuCNS-SC®) into the subretinal space of RCS rats preserves photoreceptors and visual function. To explore the possible mechanism(s) of action underlying this neuroprotective effect, we performed a detailed morphological and ultrastructure analysis of HuCNS-SC transplanted retinas using Electron Microscopy (EM)
HuCNS-SC were transplanted into the subretinal space of immunosuppressed RCS rats at P21. Histological examination of the transplanted retinas was performed by light and electron microscopy of whole mount preparations at P60 and P90. HuCNS-SC cells were identified by pre-embedding immunohistochemistry with a human specific antibody STEM121. Areas of the retina with HuCNS-SC graft (treated regions) were compared to control sections distal from the transplant site (untreated regions).
Semi-thin sections were first examined by light microscopy. In the treated regions, photoreceptor nuclei, as well as inner and outer segments were readily identified. In the untreated regions; few if any photoreceptor nuclei were identified, rod outer and inner segments were missing and a debris zone formed contiguous to the photoreceptor layer. These observations are in agreement with published data. Detailed ultrastructure analysis by EM revealed the presence of phagosomes and vesicles exhibiting the lamellar structure of outer segments within the cytosol of human cells, indicating that HuCNS-SC have phagocytic capacity in vivo, a function typically carried out by healthy retinal pigment epithelium (RPE). Finally, the outer plexiform layer (OPL) thickness appeared increased in treated regions and exhibited a remarkable preservation of the photoreceptor-bipolar-horizontal cell synaptic contacts, an observation not previously reported.
This study reveals for the first time that phagocytosis of photoreceptor outer segments by HuCNS-SC is a mechanism of retinal neuroprotection in the RCS rat. In addition to photoreceptor rescue, preservation of synaptic connections in the retina is also achieved through HuCNS-SC transplantation and likely supports maintenance of visual function. Clinical testing of HuCNS-SC in age-related macular degeneration is underway in a Phase I/II FDA-approved trial.
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