Olfactory Ensheathing Cells Inhibit Gliosis in Retinal Degeneration by Downregulation of the Müller Cell Notch Signaling Pathway

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.

Combined Transplantation of Olfactory Ensheathing Cells With Rat Neural Stem Cells Enhanced the Therapeutic Effect in the Retina of RCS Rats

“…OECs have also been found to protect visual function. Our previous work showed that OECs restore retinal function and alleviate retinal degeneration in RDD animal models via reducing the gliotic injury response of Müller cells, phagocytosing retinal outer segments, and inhibiting oxidative stress (Huo et al, 2011(Huo et al, , 2012Xie et al, 2017;Xue et al, 2017). We further confirmed that OECs can promote retinal ganglion cell survival and axonal regeneration after optic nerve injury for 3 months (Wang et al, 2017).…”

“…The OECs and NSC were tested at passage 3. The nerve growth factor receptor P75 and Nestin were used as OECs and NSCs markers, respectively (Xie et al, 2017). The OECs were fusiform shaped with elongated processes (Supplementary Figures 3A,B).…”

“…In the retina, the gliotic response from Müller cells regulates the size of the glial scar, which inhibits transplanted cells from exerting their therapeutic effect. Our previous results showed that olfactory ensheathing cells (OECs), a glial cell type originating from the neocortex of the olfactory bulb, inhibits gliosis in the retinas of RCS rats (Xie et al, 2017). Therefore, transplanting OECs with NSCs might improve the restoration of visual function in RCS rats.…”

The Regulation of Notch Signaling in Retinal Development and Regeneration

“…Since Lhx2 is associated with Notch activation in the developing retina and relies on the coordinated activities of several intrinsic factors, the interaction between Lhx2 and Notch signaling may be altered in the context of the mature retina. The transplantation of olfactory ensheathing cells into the subretinal space of rats with retinal degeneration can improve neuronal survival and prevent gliosis [82]. This appears to be due, in part, to the down-regulation of Notch signaling by MG through Notch3, and this decrease in the expression of a subset of Notch components may be mediated by matrix metalloproteinases.…”

Bridges of biomaterials promote nigrostriatal pathway regeneration

“…PCL also showed to be compatible to OEG cografting. The use of OEG and other cells which enhance axonal growth associated to biomaterials has already been tested and could be a proper strategy to adapt the artificial grafts to the repair of brain injuries.…”