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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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Rod and cone protection.A. Retinal sections stained with cresyl violet indicate substantial preservation of photoreceptors across the retina in MSC treated eyes at P90, while in control eyes (sham injected (B) and untreated (C)): only a single layer of photoreceptors remained. A1, A2 &A3: higher power images showing preservation of photoreceptors from the insets A1, A2 &A3 in A. D, E&F: confocal images showing rhodopsin (green in D) and cone arrestin (red in E) positive staining at P90 in MSC treated retina, while in sham injected retina, cone arrestin staining was dramatically reduced (F). All sections were counterstained with DAPI (blue) (scale bars equal 50 µm).
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pone-0009200-g001: Rod and cone protection.A. Retinal sections stained with cresyl violet indicate substantial preservation of photoreceptors across the retina in MSC treated eyes at P90, while in control eyes (sham injected (B) and untreated (C)): only a single layer of photoreceptors remained. A1, A2 &A3: higher power images showing preservation of photoreceptors from the insets A1, A2 &A3 in A. D, E&F: confocal images showing rhodopsin (green in D) and cone arrestin (red in E) positive staining at P90 in MSC treated retina, while in sham injected retina, cone arrestin staining was dramatically reduced (F). All sections were counterstained with DAPI (blue) (scale bars equal 50 µm).

Mentions: In the RCS rat by postnatal day (P) 90 only a single layer of photoreceptors remains compared to the 10 layers observed at P30. To investigate whether MSCs could provide a neuroprotective effect, we isolated and injected intravenously syngeneic MSCs into RCS rats at P30 (n = 12), at which time the retinal degeneration is at an early stage. Eyes were collected and processed at P90 to determine efficacy of MSC treatment in comparison to controls (sham injection (carrying medium alone): n = 8, and untreated: n = 8). Retinal sections were stained with cresyl violet for examining general retinal lamination and with photoreceptor cell-specific antibodies (rhodopsin, cone arrestin), which showed the preservation of cone and rod photoreceptors within the MSC treated animals. We found that photoreceptors were substantially rescued across the retina (Figure 1A). Although an uneven distribution of cell layer thickness was noted with more prominent rescue in peripheral than central retina. There were 5–6 layers of photoreceptors in the peripheral retina compared with 2–3 layers in the central retina (Figure 1: A1&A3 vs. A2). The retina appeared orderly laminated. In contrast, there was a single layer of photoreceptor remaining in both sham injected (Figure 1B) and untreated retinas (Figure 1C). Morphologically both rod and cone photoreceptors were rescued (Figure 1 D&E). Further analysis revealed that cone density was 18±3 cells/300 µm in retina that had received MSCs (20±2 cells/300 µm in wild type); while in control retina (Figure 1F) it was impossible to conduct meaningful counts due to severe degeneration.


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)

Rod and cone protection.A. Retinal sections stained with cresyl violet indicate substantial preservation of photoreceptors across the retina in MSC treated eyes at P90, while in control eyes (sham injected (B) and untreated (C)): only a single layer of photoreceptors remained. A1, A2 &A3: higher power images showing preservation of photoreceptors from the insets A1, A2 &A3 in A. D, E&F: confocal images showing rhodopsin (green in D) and cone arrestin (red in E) positive staining at P90 in MSC treated retina, while in sham injected retina, cone arrestin staining was dramatically reduced (F). All sections were counterstained with DAPI (blue) (scale bars equal 50 µm).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2821411&req=5

pone-0009200-g001: Rod and cone protection.A. Retinal sections stained with cresyl violet indicate substantial preservation of photoreceptors across the retina in MSC treated eyes at P90, while in control eyes (sham injected (B) and untreated (C)): only a single layer of photoreceptors remained. A1, A2 &A3: higher power images showing preservation of photoreceptors from the insets A1, A2 &A3 in A. D, E&F: confocal images showing rhodopsin (green in D) and cone arrestin (red in E) positive staining at P90 in MSC treated retina, while in sham injected retina, cone arrestin staining was dramatically reduced (F). All sections were counterstained with DAPI (blue) (scale bars equal 50 µm).
Mentions: In the RCS rat by postnatal day (P) 90 only a single layer of photoreceptors remains compared to the 10 layers observed at P30. To investigate whether MSCs could provide a neuroprotective effect, we isolated and injected intravenously syngeneic MSCs into RCS rats at P30 (n = 12), at which time the retinal degeneration is at an early stage. Eyes were collected and processed at P90 to determine efficacy of MSC treatment in comparison to controls (sham injection (carrying medium alone): n = 8, and untreated: n = 8). Retinal sections were stained with cresyl violet for examining general retinal lamination and with photoreceptor cell-specific antibodies (rhodopsin, cone arrestin), which showed the preservation of cone and rod photoreceptors within the MSC treated animals. We found that photoreceptors were substantially rescued across the retina (Figure 1A). Although an uneven distribution of cell layer thickness was noted with more prominent rescue in peripheral than central retina. There were 5–6 layers of photoreceptors in the peripheral retina compared with 2–3 layers in the central retina (Figure 1: A1&A3 vs. A2). The retina appeared orderly laminated. In contrast, there was a single layer of photoreceptor remaining in both sham injected (Figure 1B) and untreated retinas (Figure 1C). Morphologically both rod and cone photoreceptors were rescued (Figure 1 D&E). Further analysis revealed that cone density was 18±3 cells/300 µm in retina that had received MSCs (20±2 cells/300 µm in wild type); while in control retina (Figure 1F) it was impossible to conduct meaningful counts due to severe degeneration.

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