Detailed Visual Cortical Responses Generated by Retinal Sheet Transplants in Rats with Severe Retinal Degeneration.

To combat retinal degeneration, healthy fetal retinal sheets have been successfully transplanted into both rodent models and humans, with synaptic connectivity between transplant and degenerated host retina having been confirmed. In rodent studies, transplants have been shown to restore responses to flashes of light in a region of the superior colliculus corresponding to the location of the transplant in the host retina. To determine the quality and detail of visual information provided by the transplant, visual responsivity was studied here at the level of visual cortex where higher visual perception is processed. For our model, we used the transgenic Rho-S334ter line-3 rat (both sexes), which loses photoreceptors at an early age and is effectively blind at postnatal day 30. These rats received fetal retinal sheet transplants in one eye between 24 and 40 d of age. Three to 10 months following surgery, visually responsive neurons were found in regions of primary visual cortex matching the transplanted region of the retina that were as highly selective as normal rat to stimulus orientation, size, contrast, and spatial and temporal frequencies. Conversely, we found that selective response properties were largely absent in nontransplanted line-3 rats. Our data show that fetal retinal sheet transplants can result in remarkably normal visual function in visual cortex of rats with a degenerated host retina and represents a critical step toward developing an effective remedy for the visually impaired human population.SIGNIFICANCE STATEMENT Age-related macular degeneration and retinitis pigmentosa lead to profound vision loss in millions of people worldwide. Many patients lose both retinal pigment epithelium and photoreceptors. Hence, there is a great demand for the development of efficient techniques that allow for long-term vision restoration. In this study, we transplanted dissected fetal retinal sheets, which can differentiate into photoreceptors and integrate with the host retina of rats with severe retinal degeneration. Remarkably, we show that transplants generated visual responses in cortex similar in quality to normal rats. Furthermore, transplants preserved connectivity within visual cortex and the retinal relay from the lateral geniculate nucleus to visual cortex, supporting their potential application in curing vision loss associated with retinal degeneration.

Sheets of human retinal progenitor transplants improve vision in rats with severe retinal degeneration.

Loss of photoreceptors and other retinal cells is a common endpoint in retinal degenerate (RD) diseases that cause blindness. Retinal transplantation is a potential therapy to replace damaged retinal cells and improve vision. In this study, we examined the development of human fetal retinal sheets with or without their retinal pigment epithelium (RPE) transplanted to immunodeficient retinal degenerate rho S334ter-3 rats. Sheets were dissected from fetal human eyes (11-15.7 weeks gestation) and then transplanted to the subretinal space of 24-31 d old RD nude rats. Every month post surgery, eyes were imaged by high-resolution spectral-domain optical coherence tomography (SD-OCT). SD-OCT showed that transplants were placed into the subretinal space and developed laminated areas or rosettes, with clear development of plexiform layers first seen in OCT at 3 months post surgery. Several months later, as could be expected by the much slower development of human cells compared to rat cells, transplant photoreceptors developed inner and later outer segments. Retinal sections were analyzed by immunohistochemistry for human and retinal markers and confirmed the formation of several retinal subtypes within the retinal layers. Transplant cells extended processes and a lot of the cells could also be seen migrating into the host retina. At 5.8-8.6 months post surgery, selected rats were exposed to light flashes and recorded for visual responses in superior colliculus, (visual center in midbrain). Four of seven rats with transplants showed responses to flashes of light in a limited area of superior colliculus. No response with the same dim light intensity was found in age-matched RD controls (non-surgery or sham surgery). In summary, our data showed that human fetal retinal sheets transplanted to the severely disturbed subretinal space of RD nude rats develop mature photoreceptors and other retinal cells, integrate with the host and induce vision improvement.

A new immunodeficient pigmented retinal degenerate rat strain to study transplantation of human cells without immunosuppression.

PURPOSE: The goal of this study was to develop an immunodeficient rat model of retinal degeneration (RD nude rats) that will not reject transplanted human cells. METHODS: SD-Tg(S334ter)3Lav females homozygous for a mutated mouse rhodopsin transgene were mated with NTac:NIH-Whn (NIH nude) males homozygous for the Foxn1 (rnu) allele. Through selective breeding, a new stock, SD-Foxn1 Tg(S334ter)3Lav (RD nude) was generated such that all animals were homozygous for the Foxn1 (rnu) allele and either homo- or hemizygous for the S334ter transgene. PCR-based assays for both the Foxn1 (rnu) mutation and the S334ter transgene were developed for accurate genotyping. Immunodeficiency was tested by transplanting sheets of hESC-derived neural progenitor cells to the subretinal space of RD nude rats, and, as a control, NIH nude rats. Rats were killed between 8 and 184 days after surgery, and eye sections were analyzed for human, neuronal, and glial markers. RESULTS: After transplantation to RD nude and to NIH nude rats, hESC-derived neural progenitor cells differentiated to neuronal and glial cells, and migrated extensively from the transplant sheets throughout the host retina. Migration was more extensive in RD nude than in NIH nude rats. Already 8 days after transplantation, donor neuronal processes were found in the host inner plexiform layer. In addition, host glial cells extended processes into the transplants. The host retina showed the same photoreceptor degeneration pattern as in the immunocompetent SD-Tg(S334ter)3Lav rats. Recipients survived well after surgery. CONCLUSIONS: This new rat model is useful for testing the effect of human cell transplantation on the restoration of vision without interference of immunosuppression.

Trophic factors GDNF and BDNF improve function of retinal sheet transplants.

The aim of this study was to compare glial-derived neurotrophic factor (GDNF) treatment with brain-derived neurotrophic factor (BDNF) treatment of retinal transplants on restoration of visual responses in the superior colliculus (SC) of the S334ter line 3 rat model of rapid retinal degeneration (RD). RD rats (age 4-6 weeks) received subretinal transplants of intact sheets of fetal retina expressing the marker human placental alkaline phosphatase (hPAP). Experimental groups included: (1) untreated retinal sheet transplants, (2) GDNF-treated transplants, (3) BDNF-treated transplants, (4) none surgical, age-matched RD rats, (5) sham surgery RD controls, (6) progenitor cortex transplant RD controls, and (7) normal pigmented rat controls. At 2-8 months after transplantation, multi-unit visual responses were recorded from the SC using a 40 ms full-field stimulus (-5.9 to +1 log cd/m(2)) after overnight dark-adaptation. Responses were analyzed for light thresholds, spike counts, response latencies, and location within the SC. Transplants were grouped into laminated or rosetted (more disorganized) transplants based on histological analysis. Visual stimulation of control RD rats evoked no responses. In RD rats with retinal transplants, a small area of the SC corresponding to the position of the transplant in the host retina, responded to light stimulation between -4.5 and -0.08 log cd/m(2), whereas the light threshold of normal rats was at or below -5 log cd/m(2) all over the SC. Overall, responses in the SC in rats with laminated transplants had lower response thresholds and were distributed over a wider area than rats with rosetted transplants. BDNF treatment improved responses (spike counts, light thresholds and responsive areas) of rats with laminated transplants whereas GDNF treatment improved responses from rats with both laminated and rosetted (more disorganized) transplants. In conclusion, treatment of retinal transplants with GDNF and BDNF improved the restoration of visual responses in RD rats; and GDNF appears to exert greater overall restoration than BDNF.

Retina Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction.

Purpose: To study if human embryonic stem cell-derived photoreceptors could survive and function without the support of retinal pigment epithelium (RPE) after transplantation into Royal College of Surgeons rats, a rat model of retinal degeneration caused by RPE dysfunction. Methods: CSC14 human embryonic stem cells were differentiated into primordial eye structures called retinal organoids. Retinal organoids were analyzed by quantitative PCR and immunofluorescence and compared with human fetal retina. Retinal organoid sheets (30-70 day of differentiation) were transplanted into immunodeficient RCS rats, aged 44 to 56 days. The development of transplant organoids in vivo in relation to the host was examined by optical coherence tomography. Visual function was assessed by optokinetic testing, electroretinogram, and superior colliculus electrophysiologic recording. Cryostat sections were analyzed for various retinal, synaptic, and donor markers. Results: Retinal organoids showed similar gene expression to human fetal retina transplanted rats demonstrated significant improvement in visual function compared with RCS nonsurgery and sham surgery controls by ERGs at 2 months after surgery (but not later), optokinetic testing (up to 6 months after surgery) and electrophysiologic superior colliculus recordings (6-8 months after surgery). The transplanted organoids survived more than 7 months; developed photoreceptors with inner and outer segments, and other retinal cells; and were well-integrated within the host. Conclusions: This study, to our knowledge, is the first to show that transplanted photoreceptors survive and function even with host's dysfunctional RPE. Our findings suggest that transplantation of organoid sheets from stem cells may be a promising approach/therapeutic for blinding diseases.

Functional and structural assessment of retinal sheet allograft transplantation in feline hereditary retinal degeneration.

PURPOSE: To investigate whether sheets of fetal retinal allografts can integrate into the dystrophic Abyssinian cat retina with progressive rod cone degeneration. METHODS: Fetal retinal sheets (cat gestational day 42), incubated with BDNF microspheres, were transplanted to the subretinal space of four cats at an early disease stage. Cats were studied by fundus examinations, bilateral full-field flash ERGs, and indocyanine green and fluorescein angiograms up to 4 months following surgery. E42 donor and transplanted eyes were analyzed by histology and immunohistochemistry for retinal markers. RESULTS: Funduscopy and angiography showed good integration of the transplants in two of four cats, including extension of host blood vessels into the transplant and some scarring in the host. In these two, transplants were found in the subretinal space with laminated areas, with photoreceptor outer segments in normal contacts with the host retinal pigment epithelium. In some areas, transplants appeared to be well-integrated within the host neural retina. Neither of these two cats showed functional improvement in ERGs. In the other two cats, only remnants of donor tissue were left. Transplants stained for all investigated cellular markers. No PKC immunoreactivity was detected in the fetal donor retina at E42, but developed in the 4-month-old grafts. CONCLUSIONS: Fetal sheet transplants can integrate well within a degenerating cat retina and develop good lamination of photoreceptors. Functional improvement was not demonstrated by ERG in cats with well-laminated grafts. Transplants need to be further evaluated in cat host retinas with a more advanced retinal degeneration using longer follow-up times.

Retinal transplants restore visual responses: trans-synaptic tracing from visually responsive sites labels transplant neurons.

This study aimed to test the hypothesis that visual responses in the superior colliculus (SC) originate from synaptic connections between fetal retinal transplants and degenerating host retinas. Sheets of embryonic day 19 rat retina expressing human placental alkaline phosphatase were transplanted to the subretinal space of 3- to 4-week-old S334ter-line-3 rats with fast retinal degeneration. Several months later, visual responses were recorded from the SC. Attenuated pseudorabies virus that is specifically transferred between neurons at synapses (strains PRV-152, expressing green fluorescent protein (GFP) or BaBlu, expressing Escherichia colibeta-galactosidase) was injected into the visually responsive site of the SC. After survival times of 1-2 days, the virus was detected in the retina by immunohistochemistry in combination with different retinal cell markers, such as protein kinase C, recoverin, calcium-calmodulin-dependent protein kinase II and glutamine synthetase. Transplanted rats had a mean response threshold of -3.1 log cd/m(2) in a small area of the SC corresponding to the location of the graft in the retina. By 30 h after injection into this SC area, the virus traced back to host ganglion cells overlying the transplant and in close proximity to the transplant. By 2 days after injection, extensive virus label was found in the host retina and many cells in the transplant were also labeled. Virus-labeled cells in the transplant were double labeled for neuronal and glial cell markers. This study provides anatomical evidence that synaptic connections between fetal retinal transplants and host retinas contribute to the visual responses in the SC.

Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium.

PURPOSE: To demonstrate efficacy and safety of the implantation of neural retinal progenitor cell layers (sheets) with its retinal pigment epithelium (RPE) in retinitis pigmentosa (RP) and dry age-related macular degeneration (AMD) patients with 20/200 or worse vision in the surgery eye. DESIGN: Interventional nonrandomized clinical trial. METHODS: Ten patients (six RP, four AMD) received retinal implants in one eye and were followed in a phase II trial conducted in a clinical practice setting. Early Treatment Diabetic Retinopathy Study (EDTRS) was the primary outcome measure. All implant recipients and nine of 10 tissue donors were deoxyribonucleic acids typed. RESULTS: Seven patients (three RP, four AMD) showed improved EDTRS visual acuity (VA) scores. Three of these patients (one RP, two AMD) showed improvement in both eyes to the same extent. Vision in one RP patient remained the same, while vision in two RP patients decreased. One RP patient has maintained an improvement in vision from 20/800 to 20/200 ETDRS for more than five years; at the six-year examination, it was still maintained at 20/320 while the nonsurgery eye had deteriorated to hand motion vision. This patient also showed a 22.72% increase in light sensitivity at five years compared to microperimetry results at two years; the other patients showed no improved sensitivity. Although no match was found between donors and recipients, no rejection of the implanted tissue was observed clinically. CONCLUSIONS: Seven (70%) of 10 patients showed improved VA. This outcome provides clinical evidence of the safety and beneficial effect of retinal implants and corroborates results in animal models of retinal degeneration.

Transplanted hESC-Derived Retina Organoid Sheets Differentiate, Integrate, and Improve Visual Function in Retinal Degenerate Rats.

Purpose: To investigate whether sheets of retina organoids derived from human embryonic stem cells (hESCs) can differentiate, integrate, and improve visual function in an immunodeficient rat model of severe retinal degeneration (RD). Methods: 3D hESC-derived retina organoids were analyzed by quantitative PCR and immunofluorescence. Sheets dissected from retina organoids (30-65 days of differentiation) were transplanted into the subretinal space of immunodeficient rho S334ter-3 rats. Visual function was tested by optokinetic testing and electrophysiologic recording in the superior colliculus. Transplants were analyzed at 54 to 300 days postsurgery by immunohistochemistry for donor and retinal markers. Results: Retina organoids contained multiple retinal cell types, including progenitor populations capable of developing new cones and rods. After transplantation into an immunodeficient rat model of severe RD, the transplanted sheets differentiated, integrated, and produced functional photoreceptors and other retinal cells, according to the longer human developmental timetable. Maturation of the transplanted retinal cells created visual improvements that were measured by optokinetic testing and electrophysiologic recording in the superior colliculus. Immunohistochemistry analysis indicated that the donor cells were synaptically active. Extensive transplant projections could be seen within the host RD retina. Optical coherence tomography imaging monitored long-term transplant growth and survival up to 10 months postsurgery. Conclusions: These data demonstrate that the transplantation of sheets dissected from hESC-derived retina organoids is a potential therapeutic method for restoring vision in advanced stages of RD.

Behavioral evaluation of visual function of rats using a visual discrimination apparatus.

A visual discrimination apparatus was developed to evaluate the visual sensitivity of normal pigmented rats (n=13) and S334ter-line-3 retinal degenerate (RD) rats (n=15). The apparatus is a modified Y maze consisting of two chambers leading to the rats' home cage. Rats were trained to find a one-way exit door leading into their home cage, based on distinguishing between two different visual alternatives (either a dark background or black and white stripes at varying luminance levels) which were randomly displayed on the back of each chamber. Within 2 weeks of training, all rats were able to distinguish between these two visual patterns. The discrimination threshold of normal pigmented rats was a luminance level of -5.37+/-0.05 log cd/m(2); whereas the threshold level of 100-day-old RD rats was -1.14+/-0.09 log cd/m(2) with considerable variability in performance. When tested at a later age (about 150 days), the threshold level of RD rats was significantly increased (-0.82+/-0.09 log cd/m(2), p<0.03, paired t-test). This apparatus could be useful to train rats at a very early age to distinguish between two different visual stimuli and may be effective for visual functional evaluations following therapeutic interventions.

Visual functional effects of constant blue light in a retinal degenerate rat model.

Retinal degenerative conditions increase susceptibility to light damage, but rapid retinal degeneration (RD) models show less susceptibility to cyclic dim light. We investigated whether constant blue light (BL) exposure can eliminate the residual visual responses in a comparatively rapid RD rat model. Pigmented rhodopsin mutant S334ter line-3 rat pups (21 days old) were exposed for 5-6 consecutive days to constant BL. Visual behavior was evaluated with an optokinetic head tracking apparatus. Electrophysiological recordings were made from the superior colliculus (SC). S-antigen, red-green opsin and rhodopsin immunoreactive residual photoreceptors were counted. Following BL exposure, head tracking was significantly reduced at 0.25 cycles degree(-1) in 38-day-old line 3 rats. With a 0.125 cycles degree(-1) stimulus, the head tracking performance of 80-day-old BL rats were similar to that of 220-day-old no-BL-treated line-3 rats. SC recordings also revealed a significant decrease in the residual photoreceptor activity. Histological evaluation showed reduction of the rod population in the central area of the light-damaged retina. Exposure to constant BL considerably reduces the residual visual responses in a rapid degenerating RD rat model.

Structure and function of embryonic rat retinal sheet transplants.

PURPOSE: To evaluate retinal sheet transplants in S334ter-line-3 retinal degenerate rats by comparing visual responses recorded electrophysiologically with morphology based on light and electron microscopy. METHODS: S334ter-line-3 retinal degenerate rats (n = 7) received retinal sheet transplants between postnatal days 28 and 31. The donor tissue was derived from transgenic embryonic day 19 (E19) rat retinae expressing human placental alkaline phosphatase (hPAP). Fresh retinal sheets were gently transplanted into the subretinal space of the left eye with the help of a custom-made implantation tool. Selected rats (n = 5) were subjected to electrophysiologic evaluation of visual responses from the superior colliculus about 84-121 days after surgery. Transplanted eyes were processed for light microscopy (LM) and electron microscopy (EM) evaluations. RESULTS: All the transplanted rats that were evaluated for visual responses in the brain showed responses to very low light stimulation (-3.42 to -2.8 log cd/m(2)) of the eye in a small area of the superior colliculus corresponding with the placement of the transplant in the host retina. Histologic evaluation showed that most of the transplants contained well-laminated areas with correct polarity in the subretinal space. Inside the transplant areas, rosettes of photoreceptors with inner and outer segments were found. In the laminated areas, the outer segments of photoreceptors were facing the host retinal pigment epithelium (RPE). Immunohistochemical evaluation of hPAP donor cells revealed areas with specific staining of the transplants in the subretinal space. Electron microscopic evaluation showed a glial demarcation membrane between the host and the transplant, however, processes originating from the transplant were observed inside the host retina. CONCLUSIONS: Sheets of E19 rat retina transplanted into the subretinal space of S334ter-line-3 rats survived without immune rejection and continued to show visual function when tested after 3 months. Well-developed photoreceptors and many synapse types were seen within the transplants. hPAP staining showed a certain degree of integration between the host retina and the transplant suggesting that transplanted photoreceptors contributed to the restored light sensitivity.

Vision Recovery and Connectivity by Fetal Retinal Sheet Transplantation in an Immunodeficient Retinal Degenerate Rat Model.

Purpose: To characterize a recently developed model, the retinal degenerate immunodeficient S334ter line-3 rat (SD-Foxn1 Tg(S334ter)3Lav) (RD nude rat), and to test whether transplanted rat fetal retinal sheets can elicit lost responses to light. Methods: National Institutes of Health nude rats (SD-Foxn1 Tg) with normal retina were compared to RD nude rats with and without transplant for morphology and visual function. Retinal sheets from transgenic rats expressing human placental alkaline phosphatase (hPAP) were transplanted into the subretinal space of RD nude rats between postnatal day (P) 26 and P38. Transplant morphology was examined in vivo using optical coherence tomography (OCT). Visual function was assessed by optokinetic (OKN) testing, electroretinogram (ERG), and superior colliculus (SC) electrophysiology. Cryostat sections were analyzed for various retinal/synaptic markers and for the expression of donor hPAP. Results: Optical coherence tomography scans showed the placement and laminar development of retinal sheet transplants in the subretinal space. Optokinetic testing demonstrated a deficit in visual acuity in RD nude rats that was improved after retinal sheet transplantation. No ERG responses were detected in the RD nude rats with or without transplantation. Superior colliculus responses were absent in age-matched control and sham surgery RD nude rats; however, robust light-evoked responses were observed in a specific location in the SC of transplanted RD nude rats. Responsive regions corresponded to the area of transplant placement in the eye. The quality of visual responses correlated with transplant organization and placement. Conclusions: The data suggest that retinal sheet transplants integrate into the host retina of RD nude rats and recover significant visual function.

Retinal transplants evaluated by optical coherence tomography in photoreceptor degenerate rats.

Optical coherence tomography (OCT), a non-invasive method, was used for qualitative assessment of fetal retinal sheet transplants by non-invasive imaging. Rhodopsin-mutant S334ter-line-3 rats with fast retinal degeneration (28-37-day old) were transplanted with fetal retinal sheets from embryonic day (E) 18-19 pigmented normal rats. Retinal thickness measurements from transplanted (n = 51), no surgery control (n = 8), and normal pigmented rat eyes (n = 6) were obtained using a Zeiss stratus OCT-3 scanning instrument. Frozen retinal sections were stained with hematoxylin/eosin. S334ter-line-3 rats showed significant reduction in OCT retinal thickness (p<0.001) compared to normal pigmented rats at the age of 21 days. In 62% of the transplanted rats, OCT scanning revealed the presence of a subretinal graft, which was confirmed by subsequent histology. Retinal thickness in the transplant area was significantly increased compared to the area outside the transplant and to non-transplanted eyes (p<0.001). While most of the transplants with single-band OCT images (87%) had rosetted transplants, a considerable proportion of transplants having a multi-band OCT image were found to have well-laminated areas in the graft after histological evaluation. Following retinal transplantation in rodents, OCT imaging data correlated mostly with transplant morphology. OCT is a useful technique for in vivo screening and evaluation of retinal transplants. This technique determines surgical outcomes at a much earlier stage.

Retinal transplantation. A treatment strategy for retinal degenerative diseases.

Retinal transplantation is one among the various treatment strategies aimed to prevent and restore visual loss. Sheets of fetal retina with or without retinal pigment epithelium (RPE) are transplanted into the subretinal space. Retinal transplants have been shown to substantially improve visual responses in rat retinal degeneration models following retinal transplantation, based on behavior and electrophysiology. The transplantation effects may be influenced by several factors such as the age of the recipient at transplantation and the type of species used. Modified functional evaluation techniques permit better understanding of the physiological mechanisms underlying visual improvement in animal models.

Retinal transplantation--advantages of intact fetal sheets.

Retinal transplantation aims to prevent blindness and to restore eyesight, i.e., to rescue photoreceptors or to replace damaged photoreceptors with the hope of reestablishing neural circuitry. Retinal donor tissue has been transplanted as dissociated cells or intact sheets. A promising experimental paradigm is the subretinal transplantation of sheets of fetal retina with or without its attached retinal pigment epithelium (RPE) into recipient rats with retinal degeneration. As long as healthy RPE either from the host or from the graft is present, such transplants can develop lamination resembling a normal retina. Different methods have been used to demonstrate transplant/host connectivity. In two different rat retinal degeneration models, visually evoked responses can be demonstrated in an area of the superior colliculus corresponding to the placement of the transplant in the retina. In summary, sheets of fetal retina can morphologically repair an area of a degenerated retina, and there is evidence to suggest that transplants form synaptic connections with the host and restore visual responses in blind rats.

Progress in retinal sheet transplantation.

The aim of retinal transplantation is to prevent blindness and to restore eyesight, i.e. to rescue photoreceptors or to replace damaged photoreceptors with the hope of re-establishing neural circuitry. A promising experimental paradigm is the sub-retinal transplantation of sheets of fetal retina, with or without its attached retinal pigment epithelium (RPE), into recipient rats with retinal degeneration. Sheets of fetal retina have already developed their primordial circuitry. Such transplants can develop lamination resembling a normal retina dependent on the presence of healthy RPE either from the host or from the graft. In several retinal degeneration models, transplants have been shown to restore visually evoked responses in an area of the superior colliculus corresponding to the placement of the transplant in the retina. The functional effect of transplants may be due to transplant/host connectivity and/or rescue of host photoreceptors. In summary, sheets of fetal retina can morphologically repair an area of a degenerated retina, and there is evidence to suggest that transplants form synaptic connections with the host and restore visual responses in rats with retinal degeneration.

Light response differences in the superior colliculus of albino and pigmented rats.

Multi-unit visual responses to light intensities ranging from -6.46 to 0.81 logcd/m2 were recorded from the surface of the superior colliculus of dark-adapted normal pigmented and normal albino rats. Light sensitivity was significantly higher in albinos. The response onset latency was inversely proportional to the stimulus intensity. The progression of the stimulus intensity versus response onset latency curve showed a considerable difference between pigmented and albino rats. At low light levels, longer response onset latencies were recorded in pigmented rats than in albinos. This can be attributed to the transmission of rod-driven responses. The differences observed in the light response characteristics of albino rats may be indicative of their visual abnormalities.

Transplantation of neuroblastic progenitor cells as a sheet preserves and restores retinal function.

Diseases affecting the outer retina are incurable once photoreceptors are lost, and these diseases usually cause retinal pigment epithelium (RPE) dysfunction. However, the inner retina can remain functional for some time, even though retinal remodeling occurs as compensation for photoreceptor loss. If the damaged part can be replaced with neuroblastic progenitor and RPE cells as sheets with a beneficial effect on function, vision loss may be prevented and vision may be restored. This review presents an overview of the research of transplanting sheets of neural retina, with or without its RPE, to the subretinal space. In different animal models of retinal degeneration, retinal transplants can morphologically reconstruct a damaged retina, and restore visual sensitivity. Good morphological integration of transplants with the host retina can occur, whereas other transplants exhibit a glial barrier. Synaptic connections between transplant and host have been indicated by transsynaptic tracing. Retinal transplants can restore and preserve visual responses in a small area of the superior colliculus corresponding to the placement of the transplant in the retina. The beneficial effect of retinal transplantation likely involves two mechanisms: trophic effects, e.g., rescue of host cones; and synaptic connectivity between transplant and host retina.

Retinal transplantation-induced recovery of retinotectal visual function in a rodent model of retinitis pigmentosa.

PURPOSE: To map the spatiotemporal decline in retinally driven activity in the superior colliculus (SC) of transgenic S334ter-line-3 rats that express a mutated rhodopsin, which causes photoreceptor degeneration. To determine whether transplantation of fetal retinal sheets into the subretinal space of these rats can recover visual activity in the SC. METHODS: A visual stimulus was presented to the eye, and responses were recorded across the SC of untreated S334ter-line-3 rats aged 28 to 288 days. These data were used to draw a map of the developing scotoma. Intact retinal sheets from embryonic day 19 rats were transplanted into the subretinal space of S334ter-line-3 rats between 21 and 28 days of age. Responses to retinal stimulation were mapped in the SC of transplanted and sham control rats 78 to 163 days after surgery. The morphology of the retinas in all groups was examined. RESULTS: Photoreceptor cell loss in untreated rats matched the decline in visual activity in the SC. At 28 days, there was a scotoma in the area of the SC that represents the central retina and, by 63 days, it had enlarged to cover the entire retinal representation. Visual responses were evoked in 64% of rats with retinal transplants. These retinally driven responses were confined to a small, contiguous region of the SC that represents the sector of the retina where the transplant was placed. Visual responses were absent in the SC outside this area in transplant recipients and throughout the SC of untreated and sham control rats. CONCLUSIONS: Transplantation of fetal retinal sheets induced recovery of visual activity in the SC in this model of RP. The mechanisms underlying this functional recovery remain to be resolved, but these results suggest that transplantation should be further explored as a therapy for RP.