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Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology.

Wang S, Lu B, Girman S, Duan J, McFarland T, Zhang QS, Grompe M, Adamus G, Appukuttan B, Lund R - PLoS ONE (2010)

Bottom Line: There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention.Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss. both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs.These results underscore the potential application of MSCs in treating retinal degeneration.

View Article: PubMed Central - PubMed

Affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America. wangsha@ohsu.edu

ABSTRACT

Background: Retinitis pigmentosa (RP) is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs) to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS) rat, a well-established animal model for RP.

Methodology/principal findings: Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss.

Principal results: both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs.

Conclusions/significance: These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort. Therefore, MSCs may prove to be the ideal cell source for auto-cell therapy for retinal degeneration and other ocular vascular diseases.

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Preservation of visual function.A. Visual acuity tested by Optomotor response. Unrestrained animals were placed on a platform, where they tracked the grating with reflexive head movements. The acuity threshold was quantified by increasing the spatial frequency of the grating. RCS rats received MSCs and medium injection via tail vein at P30 and tested at P90. Visual acuity was significantly better in MSC treated eyes compared with controls (P<0.001). A value of 0.43 c/d was recorded, which was 78% of normal value (0.55 c/d in wild-type). B. The luminance threshold was evaluated by recording single and multiunit activity close to the surface of the superior colliculus (SC). It measures functional sensitivity across the visual field, which in turn provides a topographic indication of the magnitude and area of photoreceptor rescue across the retina. MSC treated rats recorded around P90–100 revealed significantly lower threshold than controls (P<0.005), for example, over 60% of the SC area had threshold at 2.76 log units in MSC treated eyes, no detectable response in control eyes.
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pone-0009200-g002: Preservation of visual function.A. Visual acuity tested by Optomotor response. Unrestrained animals were placed on a platform, where they tracked the grating with reflexive head movements. The acuity threshold was quantified by increasing the spatial frequency of the grating. RCS rats received MSCs and medium injection via tail vein at P30 and tested at P90. Visual acuity was significantly better in MSC treated eyes compared with controls (P<0.001). A value of 0.43 c/d was recorded, which was 78% of normal value (0.55 c/d in wild-type). B. The luminance threshold was evaluated by recording single and multiunit activity close to the surface of the superior colliculus (SC). It measures functional sensitivity across the visual field, which in turn provides a topographic indication of the magnitude and area of photoreceptor rescue across the retina. MSC treated rats recorded around P90–100 revealed significantly lower threshold than controls (P<0.005), for example, over 60% of the SC area had threshold at 2.76 log units in MSC treated eyes, no detectable response in control eyes.

Mentions: In the RCS rat, visual function deteriorates as photoreceptors are lost. Visual acuity in the RCS rat as tested by an optokinetic system (under photopic condition) has been shown to decrease with age from 0.5 cycle/degree (c/d) at P30 to 0.3 c/d at P90 [28]. This test is non-invasive, rapid and allows for repeated measurements of spatial frequency and contrast sensitivity thresholds of the optokinetic response (OKR). Another test for functional photoreceptors is a luminance threshold (LT) recording from the superior colliculus (SC) under standard background luminance level. In the RCS rat, the LT was elevated from 1.2 log units at P30 to 3 log units at P90 [29](<0.4 log units in wild rat). Although LT recording is time-consuming, it measures functional sensitivity across the visual field, which in turn provides a topographic indication of the magnitude and area of photoreceptor rescue across the whole retina. To examine whether MSCs preserved visual function after intravenous administration, we conducted the aforementioned functional tests that correlated very well with the morphological neuroprotective data. The OKR analysis revealed that there was significant difference between MSC treated and control eyes (P<0.001) (Figure 2A). An average of 0.41±0.01 c/d was recorded at P90 in MSC treated animals (n = 12), whereas 0.30±0.01 c/d in medium injected (n = 8) and 0.29±0.02 c/d in untreated (n = 8) controls were observed. Luminance threshold recordings revealed that MSC injected eyes (n = 6) produced thresholds less than 2.76 log units over 60% of the total SC area; while in controls (n = 6), no SC area produced thresholds less than 2.76 log units. Thus, MSC treated eyes had significantly lower threshold than untreated eyes (p<0.05), indicating a convincing degree of functional preservation (Figure 2B).


Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology.

Wang S, Lu B, Girman S, Duan J, McFarland T, Zhang QS, Grompe M, Adamus G, Appukuttan B, Lund R - PLoS ONE (2010)

Preservation of visual function.A. Visual acuity tested by Optomotor response. Unrestrained animals were placed on a platform, where they tracked the grating with reflexive head movements. The acuity threshold was quantified by increasing the spatial frequency of the grating. RCS rats received MSCs and medium injection via tail vein at P30 and tested at P90. Visual acuity was significantly better in MSC treated eyes compared with controls (P<0.001). A value of 0.43 c/d was recorded, which was 78% of normal value (0.55 c/d in wild-type). B. The luminance threshold was evaluated by recording single and multiunit activity close to the surface of the superior colliculus (SC). It measures functional sensitivity across the visual field, which in turn provides a topographic indication of the magnitude and area of photoreceptor rescue across the retina. MSC treated rats recorded around P90–100 revealed significantly lower threshold than controls (P<0.005), for example, over 60% of the SC area had threshold at 2.76 log units in MSC treated eyes, no detectable response in control eyes.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2821411&req=5

pone-0009200-g002: Preservation of visual function.A. Visual acuity tested by Optomotor response. Unrestrained animals were placed on a platform, where they tracked the grating with reflexive head movements. The acuity threshold was quantified by increasing the spatial frequency of the grating. RCS rats received MSCs and medium injection via tail vein at P30 and tested at P90. Visual acuity was significantly better in MSC treated eyes compared with controls (P<0.001). A value of 0.43 c/d was recorded, which was 78% of normal value (0.55 c/d in wild-type). B. The luminance threshold was evaluated by recording single and multiunit activity close to the surface of the superior colliculus (SC). It measures functional sensitivity across the visual field, which in turn provides a topographic indication of the magnitude and area of photoreceptor rescue across the retina. MSC treated rats recorded around P90–100 revealed significantly lower threshold than controls (P<0.005), for example, over 60% of the SC area had threshold at 2.76 log units in MSC treated eyes, no detectable response in control eyes.
Mentions: In the RCS rat, visual function deteriorates as photoreceptors are lost. Visual acuity in the RCS rat as tested by an optokinetic system (under photopic condition) has been shown to decrease with age from 0.5 cycle/degree (c/d) at P30 to 0.3 c/d at P90 [28]. This test is non-invasive, rapid and allows for repeated measurements of spatial frequency and contrast sensitivity thresholds of the optokinetic response (OKR). Another test for functional photoreceptors is a luminance threshold (LT) recording from the superior colliculus (SC) under standard background luminance level. In the RCS rat, the LT was elevated from 1.2 log units at P30 to 3 log units at P90 [29](<0.4 log units in wild rat). Although LT recording is time-consuming, it measures functional sensitivity across the visual field, which in turn provides a topographic indication of the magnitude and area of photoreceptor rescue across the whole retina. To examine whether MSCs preserved visual function after intravenous administration, we conducted the aforementioned functional tests that correlated very well with the morphological neuroprotective data. The OKR analysis revealed that there was significant difference between MSC treated and control eyes (P<0.001) (Figure 2A). An average of 0.41±0.01 c/d was recorded at P90 in MSC treated animals (n = 12), whereas 0.30±0.01 c/d in medium injected (n = 8) and 0.29±0.02 c/d in untreated (n = 8) controls were observed. Luminance threshold recordings revealed that MSC injected eyes (n = 6) produced thresholds less than 2.76 log units over 60% of the total SC area; while in controls (n = 6), no SC area produced thresholds less than 2.76 log units. Thus, MSC treated eyes had significantly lower threshold than untreated eyes (p<0.05), indicating a convincing degree of functional preservation (Figure 2B).

Bottom Line: There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention.Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss. both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs.These results underscore the potential application of MSCs in treating retinal degeneration.

View Article: PubMed Central - PubMed

Affiliation: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America. wangsha@ohsu.edu

ABSTRACT

Background: Retinitis pigmentosa (RP) is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs) to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS) rat, a well-established animal model for RP.

Methodology/principal findings: Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss.

Principal results: both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs.

Conclusions/significance: These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort. Therefore, MSCs may prove to be the ideal cell source for auto-cell therapy for retinal degeneration and other ocular vascular diseases.

Show MeSH
Related in: MedlinePlus