A recent study showed that an electronic chip implanted under the human retina restored some extent of vision to a blind patient. Because the device was implanted where the light-sensitive cells, the photoreceptors, should have been, this study demonstrated that it is possible to take advantage of the internal circuitry of the retina even in the absence of photoreceptors and in the presence of extensive glial and neuronal reorganization. This result strongly supports the development of cell replacement therapies for the cure of photoreceptor degeneration, provided that the cells are implanted in the same anatomical location. First, similar to other sensory neurons but in contrast to neurons lost in most degenerative diseases, photoreceptors are the first neurons of the circuit and only have to make efferent connections. Second, photoreceptors are histologically located in a restricted region of the organ. These features make them the most immediately transplantable type of neuron and interesting candidates for clinical trials involving cell transplantation.
In cell replacement therapies, the identification of the source of cells able to integrate and connect to the host tissue must be defined. For the retina, cells showing the best survival and integration rates are postmitotic rod precursors, rather than immature retinal progenitors. Given the difficulty of obtaining human fetal cells, many studies are undertaking differentiation of cells with such features starting from stem cells. Three main classes of stem cells are under investigation to be sources for in vitro photoreceptor generation: embryonic stem cells, induced pluripotent stem cells, and adult retinal stem cells. This chapter describes the current preclinical studies for in vitro generation and subsequent transplantation of photoreceptor precursors.
Ashery-Padan R, Marquardt T, Zhou X, Gruss P (2000) Pax6 activity in the lens primordium is required for lens formation and for correct placement of a single retina in the eye. Genes Dev 14:2701–11PubMedCentralPubMedCrossRefGoogle Scholar
Bartsch U, Oriyakhel W, Kenna PF et al (2008) Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into adult mice. Exp Eye Res 86:691–700. doi:10.1016/j.exer.2008.01.018PubMedCrossRefGoogle Scholar
Boucherie C, Mukherjee S, Henckaerts E, Thrasher AJ, Sowden JC, Ali RR (2013) Brief report: self-organizing neuroepithelium from human pluripotent stem cells facilitates derivation of photoreceptors. Stem Cells 31:408–414. doi:10.1002/stem.1268PubMedCrossRefGoogle Scholar
Cicero SA, Johnson D, Reyntjens S et al (2009) Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells. Proc Natl Acad Sci USA 106:6685–6690PubMedCentralPubMedCrossRefGoogle Scholar
Demontis GC, Aruta C, Comitato A, et al (2012) Functional and molecular characterization of rod-like cells from retinal stem cells derived from the adult ciliary epithelium. PLoS One 7:e33338. doi:10.1371/journal.pone.0033338 PONE-D-11-14163 [pii]
Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T, Sasai Y (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature (Lond) 472:51–56. doi:10.1038/nature09941CrossRefGoogle Scholar
Garita-Hernández M, Diaz-Corrales F, Lukovic D et al (2013) Hypoxia increases the yield of photoreceptors differentiating from mouse embryonic stem cells and improves the modeling of retinogenesis in vitro. Stem Cells 31:966–978. doi:10.1002/stem.1339PubMedCrossRefGoogle Scholar
Gualdoni S, Baron M, Lakowski J et al (2010) Adult ciliary epithelial cells, previously identified as retinal stem cells with potential for retinal repair, fail to differentiate into new rod photoreceptors. Stem Cells 28:1048–1059PubMedCrossRefGoogle Scholar
Hambright D, Park KY, Brooks M et al (2012) Long-term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un-immunosuppressed mouse retina. Mol Vis 18:920–936PubMedCentralPubMedGoogle Scholar
Mellough CB, Sernagor E, Moreno-Gimeno I et al (2012) Efficient stage-specific differentiation of human pluripotent stem cells toward retinal photoreceptor cells. Stem Cells 30:673–686. doi:10.1002/stem.1037PubMedCrossRefGoogle Scholar
Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, Saito K, Yonemura S, Eiraku M, Sasai Y (2012) Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10:771–785. doi:10.1016/j.stem.2012.05.009PubMedCrossRefGoogle Scholar
Ogilvie JM, Speck JD, Lett JM, Fleming TT (1999) A reliable method for organ culture of neonatal mouse retina with long-term survival. J Neurosci Methods 87:57–65PubMedCrossRefGoogle Scholar
Osakada F, Ikeda H, Mandai M et al (2008) Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol 26:215–224. doi:10.1038/nbt1384PubMedCrossRefGoogle Scholar