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Protection of visual functions by human neural progenitors in a rat model of retinal disease.

Gamm DM, Wang S, Lu B, Girman S, Holmes T, Bischoff N, Shearer RL, Sauvé Y, Capowski E, Svendsen CN, Lund RD - PLoS ONE (2007)

Bottom Line: Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus.Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor.A concomitant preservation of host cone photoreceptors was also observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States of America. dgamm@wisc.edu

ABSTRACT

Background: A promising clinical application for stem and progenitor cell transplantation is in rescue therapy for degenerative diseases. This strategy seeks to preserve rather than restore host tissue function by taking advantage of unique properties often displayed by these versatile cells. In studies using different neurodegenerative disease models, transplanted human neural progenitor cells (hNPC) protected dying host neurons within both the brain and spinal cord. Based on these reports, we explored the potential of hNPC transplantation to rescue visual function in an animal model of retinal degeneration, the Royal College of Surgeons rat.

Methodology/principal findings: Animals received unilateral subretinal injections of hNPC or medium alone at an age preceding major photoreceptor loss. Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus. At 90-100 days postnatal, a time point when untreated rats exhibit little or no retinal or visual function, hNPC-treated eyes retained substantial retinal electrical activity and visual field with near-normal visual acuity. Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor. Histological examination at 150 days postnatal showed hNPC had formed a nearly continuous pigmented layer between the neural retina and retinal pigment epithelium, as well as distributed within the inner retina. A concomitant preservation of host cone photoreceptors was also observed.

Conclusions/significance: Wild type and genetically modified human neural progenitor cells survive for prolonged periods, migrate extensively, secrete growth factors and rescue visual functions following subretinal transplantation in the Royal College of Surgeons rat. These results underscore the potential therapeutic utility of hNPC in the treatment of retinal degenerative diseases and suggest potential mechanisms underlying their effect in vivo.

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Visual field is preserved in eyes receiving human neural progenitor cell grafts. Luminance threshold responses were recorded at approximately P100 from multiple points within the superior colliculus (SC) contralateral to the eye being tested. This method quantifies functional sensitivity to light across the visual field of an eye. The topographical map depicts the luminance threshold responses (measured in log units relative to background illumination of 0.02 cd/m2) at 15 points within the SC opposite the cell-injected eye of a best-performing animal at P104 (right side of figure). SC recordings (16 points) opposite the fellow, untreated eye (left side of figure) served as an internal control. Both hNPCctx–GDNF and hNPCctx transplant recipients were included in the cell-injected group, which consisted of a select population of eyes that displayed superior performance on spatial visual acuity testing. Recordings falling at or below a threshold of 2.0 log units are indicated with unfilled ovals, while recordings above 2.0 are demarcated with filled ovals.
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pone-0000338-g004: Visual field is preserved in eyes receiving human neural progenitor cell grafts. Luminance threshold responses were recorded at approximately P100 from multiple points within the superior colliculus (SC) contralateral to the eye being tested. This method quantifies functional sensitivity to light across the visual field of an eye. The topographical map depicts the luminance threshold responses (measured in log units relative to background illumination of 0.02 cd/m2) at 15 points within the SC opposite the cell-injected eye of a best-performing animal at P104 (right side of figure). SC recordings (16 points) opposite the fellow, untreated eye (left side of figure) served as an internal control. Both hNPCctx–GDNF and hNPCctx transplant recipients were included in the cell-injected group, which consisted of a select population of eyes that displayed superior performance on spatial visual acuity testing. Recordings falling at or below a threshold of 2.0 log units are indicated with unfilled ovals, while recordings above 2.0 are demarcated with filled ovals.

Mentions: Luminance threshold recordings from the SC measure functional sensitivity across the visual field, which in turn provides a geographic indication of the magnitude and area of photoreceptor rescue across the retina [56]. In dystrophic RCS rats, threshold levels at P100 are greater than 3.0 log units above the background level of 0.02 log candela/m2. This is in comparison to non-dystrophic rats, which possess threshold levels less than 0.6 log units above background [48]. For the present study, recordings were made in a combined set of cell-injected animals who received either hNPCctx or hNPCctx-GDNF. Eyes were specifically chosen from either group based on their superior performance on optomotor testing; therefore, comparisons between the hNPCctx and hNPCctx-GDNF groups are not appropriate. Overall, cell-injected eyes (n = 10) performed significantly better than untreated eyes (n = 5) or those receiving sham injections (n = 3) (Figure 4 and Table 2). Specifically, 8.0±5.8% of the SC area of cell-injected eyes produced thresholds less than 0.8 log units, 22.0±8.5% produced thresholds less than 1.5 log units and 67.7±10.0% yielded thresholds less than 2.1 log units, with best test points falling within the normal, non-dystrophic range. These results are in contrast to sham-injected eyes, where only 14.8±8.3% of the SC area yielded thresholds below 2.1 log units.


Protection of visual functions by human neural progenitors in a rat model of retinal disease.

Gamm DM, Wang S, Lu B, Girman S, Holmes T, Bischoff N, Shearer RL, Sauvé Y, Capowski E, Svendsen CN, Lund RD - PLoS ONE (2007)

Visual field is preserved in eyes receiving human neural progenitor cell grafts. Luminance threshold responses were recorded at approximately P100 from multiple points within the superior colliculus (SC) contralateral to the eye being tested. This method quantifies functional sensitivity to light across the visual field of an eye. The topographical map depicts the luminance threshold responses (measured in log units relative to background illumination of 0.02 cd/m2) at 15 points within the SC opposite the cell-injected eye of a best-performing animal at P104 (right side of figure). SC recordings (16 points) opposite the fellow, untreated eye (left side of figure) served as an internal control. Both hNPCctx–GDNF and hNPCctx transplant recipients were included in the cell-injected group, which consisted of a select population of eyes that displayed superior performance on spatial visual acuity testing. Recordings falling at or below a threshold of 2.0 log units are indicated with unfilled ovals, while recordings above 2.0 are demarcated with filled ovals.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1828619&req=5

pone-0000338-g004: Visual field is preserved in eyes receiving human neural progenitor cell grafts. Luminance threshold responses were recorded at approximately P100 from multiple points within the superior colliculus (SC) contralateral to the eye being tested. This method quantifies functional sensitivity to light across the visual field of an eye. The topographical map depicts the luminance threshold responses (measured in log units relative to background illumination of 0.02 cd/m2) at 15 points within the SC opposite the cell-injected eye of a best-performing animal at P104 (right side of figure). SC recordings (16 points) opposite the fellow, untreated eye (left side of figure) served as an internal control. Both hNPCctx–GDNF and hNPCctx transplant recipients were included in the cell-injected group, which consisted of a select population of eyes that displayed superior performance on spatial visual acuity testing. Recordings falling at or below a threshold of 2.0 log units are indicated with unfilled ovals, while recordings above 2.0 are demarcated with filled ovals.
Mentions: Luminance threshold recordings from the SC measure functional sensitivity across the visual field, which in turn provides a geographic indication of the magnitude and area of photoreceptor rescue across the retina [56]. In dystrophic RCS rats, threshold levels at P100 are greater than 3.0 log units above the background level of 0.02 log candela/m2. This is in comparison to non-dystrophic rats, which possess threshold levels less than 0.6 log units above background [48]. For the present study, recordings were made in a combined set of cell-injected animals who received either hNPCctx or hNPCctx-GDNF. Eyes were specifically chosen from either group based on their superior performance on optomotor testing; therefore, comparisons between the hNPCctx and hNPCctx-GDNF groups are not appropriate. Overall, cell-injected eyes (n = 10) performed significantly better than untreated eyes (n = 5) or those receiving sham injections (n = 3) (Figure 4 and Table 2). Specifically, 8.0±5.8% of the SC area of cell-injected eyes produced thresholds less than 0.8 log units, 22.0±8.5% produced thresholds less than 1.5 log units and 67.7±10.0% yielded thresholds less than 2.1 log units, with best test points falling within the normal, non-dystrophic range. These results are in contrast to sham-injected eyes, where only 14.8±8.3% of the SC area yielded thresholds below 2.1 log units.

Bottom Line: Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus.Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor.A concomitant preservation of host cone photoreceptors was also observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States of America. dgamm@wisc.edu

ABSTRACT

Background: A promising clinical application for stem and progenitor cell transplantation is in rescue therapy for degenerative diseases. This strategy seeks to preserve rather than restore host tissue function by taking advantage of unique properties often displayed by these versatile cells. In studies using different neurodegenerative disease models, transplanted human neural progenitor cells (hNPC) protected dying host neurons within both the brain and spinal cord. Based on these reports, we explored the potential of hNPC transplantation to rescue visual function in an animal model of retinal degeneration, the Royal College of Surgeons rat.

Methodology/principal findings: Animals received unilateral subretinal injections of hNPC or medium alone at an age preceding major photoreceptor loss. Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus. At 90-100 days postnatal, a time point when untreated rats exhibit little or no retinal or visual function, hNPC-treated eyes retained substantial retinal electrical activity and visual field with near-normal visual acuity. Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor. Histological examination at 150 days postnatal showed hNPC had formed a nearly continuous pigmented layer between the neural retina and retinal pigment epithelium, as well as distributed within the inner retina. A concomitant preservation of host cone photoreceptors was also observed.

Conclusions/significance: Wild type and genetically modified human neural progenitor cells survive for prolonged periods, migrate extensively, secrete growth factors and rescue visual functions following subretinal transplantation in the Royal College of Surgeons rat. These results underscore the potential therapeutic utility of hNPC in the treatment of retinal degenerative diseases and suggest potential mechanisms underlying their effect in vivo.

Show MeSH
Related in: MedlinePlus