Photoreceptor Transplants Increase Host Cone Survival in the Retinal Degeneration (rd) Mouse

Mohand‐Saïd, Saddek; Hicks, David G.; Silva, Manuel; D, Tran-Minh; Deudon-Combe, A.; Dreyfus, H.; Silverman, Martin S.; Ogilvie, Judith Mosinger; Tenkova, Tatyana; Sahel, J

doi:10.1159/000268027

Cited by 87 publications

(67 citation statements)

References 18 publications

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“…The existence of diffusible trophic factors influencing photoreceptor survival initially was suggested from studies of chimeric normal and dystrophic rat retina in which regions of rod survival overgrew normal retinal pigmented epithelium (31). This hypothesis is supported by our recent findings (20) that transplantation of isolated outer nuclear layer fragments from C57BL͞6 mice (and hence 97% pure in rods) promote survival of cones in the rd host retina, including at distance from the transplantation site (20). Taken together, these studies support a role for cellular interactions in cone survival within dystrophic and possibly normal retina.…”

Section: Discussionsupporting

confidence: 65%

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Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Mohand‐Saïd¹,

Deudon-Combe²,

Hicks³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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185

127

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The role of cellular interactions in the mechanism of secondary cone photoreceptor degeneration in inherited retinal degenerations in which the mutation specifically affects rod photoreceptors was studied. We developed an organ culture model of whole retinas from 5-week-old mice carrying the retinal degeneration mutation, which at this age contain few remaining rods and numerous surviving cones cocultured with primary cultures of mixed cells from postnatal day 8 normal-sighted mice (C57BL͞6) retinas or retinal explants from normal (C57BL͞6) or dystrophic (C3H͞He) 5-week-old mice. After 7 days, the numbers of residual cone photoreceptors were quantified after specific peanut lectin or anti-arrestin antibody labeling by using an unbiased stereological approach. Examination of organ cultured retinas revealed significantly greater numbers of surviving cones (15-20%) if cultured in the presence of retinas containing normal rods as compared with controls or cocultures with rod-deprived retinas. These data indicate the existence of a diffusible trophic factor released from retinas containing rod cells and acting on retinas in which only cones are present. Because cones are responsible for high acuity and color vision, such data could have important implications not only for eventual therapeutic approaches to human retinal degenerations but also to define interactions between retinal photoreceptor types.Despite recent advances, our understanding of the mechanisms underlying visual malfunction and cell loss in retinitis pigmentosa (RP) has provided few clinically significant clues to improve retinal cell survival (1-3). RP forms a group of inherited photoreceptor dystrophies characterized largely by early features of rod photoreceptor impairment (1, 4). Most identified forms of RP are caused by defects in proteins restricted to rod photoreceptors (5-8). Yet, at various stages of the disease, a loss of the photopic function reflecting degeneration of cone photoreceptors is found consistently (1, 4). Of extreme importance for the patient, cone cell death and its functional consequences appear to be secondary events. No current data exist to account for cone cell death, but observations made on animal models of RP provide arguments for cone survival depending on the presence of rods. In several models with selective elimination of rods, secondary loss of cones is observed (9-11). The cause of rod cell death in these animals, either transgenic or spontaneous mutants, cannot account for direct cone cell loss (9-17). Putative mechanisms of cone cell death include the liberation of endotoxins by degenerating rods, environmental alteration, or deprivation of rod-derived trophic factor(s). Recent studies using chimeras of normal and transgenic mice carrying mutations in rods showed that photoreceptor cell death was diffuse rather than restricted to areas with mutations in rods, providing evidence for a role of cellular interactions between photoreceptors in survival and degeneration of these cells (18). Based on these dat...

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Section: Discussionsupporting

confidence: 65%

“…This model appears appropriate to test the hypothesis of the dependence of cones on the viability of rods. Indeed, we found that transplantation of rod-rich photoreceptor transplants to these animals at an age when most rods have disappeared induced a significant increase in host cone survival (20).…”

mentioning

confidence: 85%

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Mohand‐Saïd¹,

Deudon-Combe²,

Hicks³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

185

127

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“…Although there is evidence that transplants themselves are functional (Adolph et al, 1994;Seiler et al, 1999) and that some degree of graft-host integration can occur after retinal transplantation (Ehinger et al, 1991;Silverman et al, 1992;Gouras et al, 1994;Aramant and Seiler, 1995;Seiler and Aramant, 1998;Ghosh et al, 1999;Kwan et al, 1999;Gouras and Tanabe, 2003;Zhang et al, 2003), the presence of definite functional synaptic connections has not yet been reported. As a second potential mechanism of action, the transplanted tissue could provide an indirect effect via the release of humoral factors that could prevent or retard the degeneration of the remaining host photoreceptors (Mohand-Said et al, 1997, 2000Fintz et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Restoration of visual responses following transplantation of intact retinal sheets in rd mice

Arai

Thomas

Seiler

et al. 2004

Experimental Eye Research

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Purpose. To correlate the functional outcomes with histologic findings following transplantation of fetal retinal sheets in rd mice, and to investigate the mechanisms of visual function restoration.Methods. Twenty-one postnatal day 31 -38 rd/rd (C3H/HeJ) mice were transplanted in one eye with retinal sheets (1·0 £ 0·4 mm) obtained from embryonic day (E) 17 enhanced-green-fluorescent protein (eGFP) mice. Five mice underwent sham surgery without insertion of tissue. Four to five weeks after transplantation, visual responses to a light flash were recorded across the superior colliculus (SC) in seven eyes of seven transplanted mice that had clear corneas and lenses, and in all five sham surgery mice. Following the SC recording, the eyes were enucleated and processed for immunohistochemistry and examined using confocal microscopy.Results. In three out of the seven eyes (43%), positive responses were recorded in the SC in an area topographically corresponding to the placement of the transplant in the host retina. No responses were recorded in the untreated eyes of 5-week-old and 9-week-old rd/rd mice, and in the 9-week-old sham surgery mice. In contrast, visual responses were recorded over the entire SC in normal eyes. The response onset latencies of the 3 transplanted mice with responses were similar to those of normal control mice. The organization of the graft did not appear to correlate as expected with the electrophysiology results, as eyes with well-organized, laminated grafts showed no response whereas the three light-responsive eyes had rosetted or disorganized grafts. All three light-responsive eyes demonstrated much higher levels of recoverin immunoreactivity in the host retina overlying the graft compared with untreated age-matched rd/rd mice.Conclusion. Restoration of the SC visual response does not appear to depend on a well-organized transplant in the rd mouse. Increased recoverin-staining in the host retina in light-responsive animals suggested that host cone rescue was the likely mechanism of vision restoration in this transplant model. q

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“…First, the visual responses in the caudal SC were observed only in a very small area of the SC precisely corresponding to the placement of the graft in the retina. If a trophic effect of the transplant on host photoreceptors was the cause, it should have an effect on a larger retinal area, as has been observed in rd mice with rod photoreceptor transplants (Mohand-Said et al, 1997). Second, based on S-antigen immunoreactivity, no difference was observed in the number of remaining cone photoreceptors near the transplant site and other areas of the host retina.…”

Section: Mechanism Underlying the Visual Restorationmentioning

confidence: 91%

Superior colliculus responses to light – preserved by transplantation in a slow degeneration rat model

Thomas

Seiler

Sadda

et al. 2004

Experimental Eye Research

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Purpose. To determine whether retinal transplantation can preserve visual responses in the superior colliculus (SC) of the S334ter-line-5 rat, a transgenic model for slow photoreceptor degeneration, which is more similar to human retinitis pigmentosa than the fast degeneration line 3 S334ter rat.Methods. Visual responses to a light flash were recorded in the SC. Rats that had received embryonic day (E) 19 -20 fetal retinal sheet transplants at the age of 26 -30 days were tested at the ages of 200-254 days. Controls were age-matched rats without surgery and with sham surgery. As a baseline, in no-surgery line-5 rats, the temporal pattern of visual sensitivity loss was evaluated electrophysiologically in the SC from 60 days up to one year of age.Results. In untreated S334ter-line-5 rats, decline in visual sensitivity in the SC was parallel to the photoreceptor loss. At 109 day of age, a relative scotoma developed in the area of the SC corresponding to the nasal retinal region. At 200-254 days of age, the majority of the SC was devoid of any light-driven responses. In contrast, at this time point, transplanted rats with 'good' retinal grafts with normal lamination had visual responses in the caudal region of the SC, the area corresponding topographically to the transplant location in the retina. In these rats, the various parameters of SC responses such as the latency of the onset of the visual response, the response peak amplitude and the consistency of the visual response were significantly different from the control groups (no-surgery, sham surgery, 'poor' transplants) and were more comparable to normal albino rats, however, with a slightly longer latency (70-90 vs. 30 -50 msec).Conclusions. Fetal retinal sheet transplantation showed a long-term rescue effect on visual function in this animal model of slow photoreceptor degeneration. q

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Photoreceptor Transplants Increase Host Cone Survival in the Retinal Degeneration (rd) Mouse

Cited by 87 publications

References 18 publications

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Restoration of visual responses following transplantation of intact retinal sheets in rd mice

Superior colliculus responses to light – preserved by transplantation in a slow degeneration rat model

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