Retinal Incorporation and Differentiation of Neural Precursors Derived from Human Embryonic Stem Cells

Abstract

Retinal and macular degenerations are a major cause of blindness. Cell transplantation is a possible therapeutic approach for the replacement of degenerating retinal cells. Here, we studied the potential of human embryonic stem cells (hESCs) to survive, integrate, and differentiate into retinal cells after intraocular transplantation. Highly enriched cultures of neural precursors (NPs) expressing transcripts of key regulatory genes of retinal development were developed from the hESCs. After spontaneous differentiation in vitro, the NPs gave rise to progeny expressing markers of retinal progenitors and photoreceptor development, though this was uncommon and cells expressing markers of mature photoreceptors were not observed. After transplantation into rat eyes, the NPs survived for 16 weeks, migrated large distances, and integrated in the host retina. Teratoma tumors were not observed. Human cells expressing rhodopsin, blue cone opsin, and neural retina leucine zipper transcription factor were observed in subretinal grafts, but not within vitreal and inner retinal grafts. The results suggest that hESCs have the potential to differentiate into retinal cells and that the subretinal microenvironment supports their differentiation toward a photoreceptor fate. This may be the first step toward further developments that eventually may allow the use of hESCs for transplantation in retinal degenerations. STEM CELLS 2006;24:246 -257

Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL

“…In utero infection of mouse embryonic retinas (57) with Nrl may also demonstrate whether we can stretch the developmental potential of retinal progenitors. Our studies give rise to the prospect of exploiting the plastic nature of retinal precursors to replenish dying rods in degenerative retinal diseases by ectopic NRL expression in retinal stem cells (58,59) or by transplantation of NRL-expressing progenitors (60).…”

Stem Cells for Retinal Replacement Therapy

“…When transplanted into the retina, ESC-derived NSCs show limited incorporation and differentiation into photoreceptor cell fates. Importantly, functional rescue of the outer retina in an animal model is observed after transplantation of ESC-NSCs [48][49][50]. Teratomas were not observed after transplantation of ESC-NSCs, although tumors were observed with related neurally selected ESCs [51].…”

Modeling early retinal development with human embryonic and induced pluripotent stem cells

“…To date, hESC studies have focused on the derivation of subsets of retinal cell populations, with emphasis on the production of either retinal progenitors (5,6) or more mature cells such as retinal pigment epithelium (RPE) (3,4) or photoreceptors (7). Many of these studies used various exogenous factors to increase the percentage of early retinal cell types present within the mixed population of differentiating hESCs.…”

“…However, despite these recent advances, the ability of hESCs to produce a highly enriched population of cells at the earliest stage of retinal specification that can progress through each of the key developmental stages of the retina has yet to be demonstrated. Moreover, the timing of onset of selected stages in retinal development has varied widely among published human pluripotent stem cell differentiation protocols, none of which approximated the timeline of normal human retinogenesis (5)(6)(7)(8)(9).…”