Results from this study show that neural progenitor cells derived from developing human cortex promote long-term preservation of vision after subretinal transplantation in the RCS rat. Using three independent tests performed at P90-100, hNPCctx
- and hNPCctx
-GDNF-transplanted eyes demonstrated retention of visual functions at levels among the best documented in the RCS rat model 
. These results correlated with survival of photoreceptors, including cone cells, which are required for optimal daylight vision. In contrast, sham injections of medium alone failed to achieve significant sustained functional rescue, consistent with previous studies. It has also been shown that fibroblasts 
and placenta-derived progenitor cells 
are unable to maintain visual functions long-term, further indicating that the rescue effects seen in the RCS rat model are not the result of a non-specific event. Of note, while vision rescue requires preservation of some functional photoreceptors, the mere presence of photoreceptor cells in the ONL of transplanted RCS rats does not assure function 
. Thus, we chose to emphasize quantitative functional responses to hNPCctx
transplantation and support these findings with a more qualitative investigation of the host anatomical impact.
Histological examination reveals that hNPCctx
survive, migrate and assume two substantially different appearances and distributions following transplantation into the subretinal space of RCS rats. These findings were seen regardless of whether the cells were previously transduced with a GDNF-expressing construct. One population is non-pigmented and diffusely distributed within the inner retina, while the other is a pigment granule-containing, RPE-like layer located between the host neurosensory retina and RPE. In previous studies using other donor cell types, significant intraretinal migration was not seen 
, nor were pigment granules found in donor cells not originally derived from RPE 
. However, similar to other reports introducing forebrain–derived stem cells into the retina 
, donor cells used in this study did not express markers typical of host retinal cells. Our observations imply that donor cell location within host tissue can influence their apparent phenotype, even though they lack critical markers of the cells they come to resemble.
The mechanism by which human neural progenitor cells exert their effects within the retina is not wholly clear, but is likely due in part to growth factor production 
and possibly also to the manifestation of some RPE-like properties. With respect to factor production, we have detailed at least two factors, IGF-1 and FGF-2, that hNPCctx
produce in vitro
that could be effective in promoting vision and photoreceptor preservation. A more comprehensive survey may identify others. Thus, transplanted hNPCctx
have the potential to release multiple growth factors, which may act synergistically to slow photoreceptor degeneration 
. The superior performance of hNPCctx
-GDNF is consistent with both the known role of GDNF as a neuroprotective molecule within the retina 
and the established ability of hNPCctx
to function as a cell-based drug delivery vector in diverse CNS tissues 
. The additional capacity of hNPCctx
to migrate extensively within the subretinal space and inner retina allows them to deliver molecules of therapeutic interest not only for outer retinal disease (e.g.
, retinitis pigmentosa and age-related macular degeneration), but inner retinal disorders as well (e.g.
, glaucoma). Panretinal donor cell migration also affords better access to Müller glia, which bind and mediate host responses to some neurotrophic factors, including GDNF 
The additional question of whether hNPCctx
might mimic some of the functions of RPE is an intriguing one. A population of these cells forms a layer deep to the photoreceptors, where they contain intracellular pigment granules and appear superficially like an extra RPE layer, even though they do not express at least two characteristic RPE proteins. The presence of intracellular pigment granules along with the absence of a subretinal cellular debris zone raise the possibility that these donor cells have (or acquire) the capacity to phagocytose surrounding waste material. As this is one function of healthy RPE 
, such activity may contribute to the cell transplant-mediated rescue observed, a possibility that is being explored further.
The fact that donor cells continue to divide until P150 is a matter of both concern and optimism. Previous work has shown that ES-derived RPE cells can develop teratomas 
, although not in all cases 
. However, in the present study there is no evidence of untoward donor cell proliferation or tumor formation up to at least 130 days post-transplantation, suggesting that cell division is a regulated or balanced event. Indeed, persistent cell division may contribute to the sustained high performance of hNPCctx
transplant recipients over time. Even so, later time points are needed to ensure that tumors never form within the retina after transplantation of hNPCctx
In summary, transplanted hNPCctx
display a novel profile of properties that produce profound rescue of visual functions in the RCS rat, an animal model of photoreceptor loss secondary to RPE dysfunction. The potential for native or modified hNPCctx
to deliver neurotrophins and rescue cones and photopic vision in primary rod degeneration models also needs to be assessed. However, current results point to a possible role for hNPCctx
in the treatment of at least some forms of human retinal degenerative diseases and highlight the versatility and efficacy of these cells as therapeutic tools in a broad range of neurodegenerative disorders 
. A current clinical trial investigating the use of transplanted human neural stem cells in Batten disease 
will address questions concerning the safety of this cell type and provide important background for contemplating their clinical application in retinal disease.