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Shu-Zhen Wang, Li He, Run-Tao Yan; The RPE as stem-like cells for retinal regeneration in adult mouse. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3171.
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© ARVO (1962-2015); The Authors (2016-present)
Regenerating neurons and neural connection has been selected as NEI Audacious Goal. Our laboratory investigates the possibility of using a regulatory gene, ngn1 or ngn3, to reprogram the RPE for retinal regeneration in the mouse eye. In previous studies we found ectopic retinal tissue/cells in some PVMD2-ngn1 and PRPE65-ngn3 transgenic mice. This study examines whether (1) the RPE in adult mouse could undergo the gene-directed reprogramming, (2) the RPE, which plays a crucial role in the function and health of the retina, was preserved in those transgenic animals, and (3) Müller glia was involved.
Cryosections of eyes from adult transgenic mice with photoreceptor-like cells in the subretinal space were immunostained with antibodies that recognize RPE proteins, photoreceptor protein Recoverin (Rcv), or Müller glia. The presence of a hybrid or mixed cell type, i.e., a cell co-expressing markers that otherwise are exclusive for either RPE or photoreceptor cells, was used as an indication of the cell amid RPE-to-photoreceptor reprogramming process.
At places with Rcv+ cells in the subretinal space, the highly melanized RPE was present and was immuno-positive for RPE proteins: CRALBP, Cytokeratin-18, Ezrin, and RPE65. Ezrin and RPE65 were also detected in some of the ectopic Rcv+ cells, especially in those containing some pigment granules, which otherwise are abundantly present in normal RPE cells. Otx2, a transcriptional factor known to be important for RPE differentiation and maintenance of RPE properties and to be down-regulated during the RPE-to-retina transdifferentiation observed in amphibians and chicken, was detected in the RPE at most places and not in regions where RPE was seemingly undergoing RPE-to-photoreceptor reprogramming. Some cells within the territory occupied by the subretinal Rcv+ cells were immuno-positive for Müller glia makers GS and CRALBP, and a few Rcv+/GS+ double-labeled cells were observed.
The results suggest that the RPE in adult mice can be guided by ngn1 or ngn3 to produce retinal cells, including Müller glia, and can regenerate itself afterward. This raises a possibility using the RPE as stem-like cells for retinal regeneration in adult mammals.
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