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Olfactory Ensheathing Cells Inhibit Gliosis in Retinal Degeneration by Downregulation of the Müller Cell Notch Signaling Pathway.
- Source :
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Cell transplantation [Cell Transplant] 2017 Jun 09; Vol. 26 (6), pp. 967-982. Date of Electronic Publication: 2017 Feb 09. - Publication Year :
- 2017
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Abstract
- Retinal regeneration and self-repair, whether in response to injury or degenerative disease, are severely impeded by glial scar formation by Müller cells (specialized retinal macroglia). We have previously demonstrated that the activation of Müller cells and gliosis in the degenerative retina are significantly suppressed by the subretinal transplantation of a mixture of olfactory ensheathing cells (OECs) and olfactory nerve fibroblasts. However, the underlying molecular mechanism has remained elusive. Here we transplanted purified rat OECs into the subretinal space of pigmented Royal College of Surgeons (RCS) rats, a classic rodent model of retinal degeneration. Using behavioral testing and electroretinography, we confirmed that the grafted OECs preserved the visual function of rats for 8 weeks, relative to vehicle controls (phosphate-buffered saline). Histological evaluation of outer nuclear layer thickness and composition demonstrated that more photoreceptors and ON-bipolar cells were preserved in the retinas of OEC-treated RCS rats than in controls. The grafted OECs migrated into the outer plexiform layer, inner nuclear layer, and inner plexiform layer. They interacted directly with Müller cells in the retina of RCS rats, in three distinct patterns, and secreted matrix metalloproteinases 2 and 3. Previous studies have demonstrated that rat OECs express delta-like ligand (DLL), while Müller cells express Notch3, the receptor for DLL. Here we found that the grafted OECs significantly decreased the expression, by retinal cells, of Notch signaling pathway components (including Notch3, Notch4, DLL1, DLL4, Jagged1, Hes1, and Hes5) 2 weeks after the cell transplantation and that this effect persisted for a further 2 weeks. Based on these findings, we suggest that transplanted OECs inhibit the activation of Müller cells and the associated gliosis, at least partly through suppression of the Notch pathway.
- Subjects :
- Animals
Basic Helix-Loop-Helix Transcription Factors genetics
Basic Helix-Loop-Helix Transcription Factors metabolism
Cells, Cultured
Gliosis metabolism
Intercellular Signaling Peptides and Proteins genetics
Intercellular Signaling Peptides and Proteins metabolism
Jagged-1 Protein genetics
Jagged-1 Protein metabolism
Matrix Metalloproteinase 2 genetics
Matrix Metalloproteinase 2 metabolism
Matrix Metalloproteinase 3 genetics
Matrix Metalloproteinase 3 metabolism
Rats
Receptor, Notch3 genetics
Receptor, Notch3 metabolism
Receptor, Notch4 genetics
Receptor, Notch4 metabolism
Receptors, Notch genetics
Repressor Proteins genetics
Repressor Proteins metabolism
Retinitis Pigmentosa metabolism
Retinitis Pigmentosa therapy
Signal Transduction physiology
Transcription Factor HES-1 genetics
Transcription Factor HES-1 metabolism
Down-Regulation
Ependymoglial Cells metabolism
Gliosis therapy
Olfactory Bulb cytology
Receptors, Notch metabolism
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1555-3892
- Volume :
- 26
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 28185609
- Full Text :
- https://doi.org/10.3727/096368917X694994