Abstract
Cell-based therapies are increasingly recognized as a potential strategy to treat retinal neurodegenerative disease. Their administration, however, is normally indirect and complex, often with an inability to assess in real time their effects on cell death and their migration/integration into the host retina. In the present study, using a partial optic nerve transection (pONT) rat model, we describe a new method of Schwann cell (SC) delivery (direct application to injured optic nerve sheath, SC/DONS), which was compared with intravitreal SC delivery (SC/IVT). Both SC/DONS and SC/IVT were able to be assessed in vivo using imaging to visualize retinal ganglion cell (RGC) apoptosis and SC retinal integration. RGC death in the pONT model was best fitted to the one-phase exponential decay model. Although both SC/DONS and SC/IVT altered the temporal course of RGC degeneration in pONT, SC/DONS resulted in delayed but long-lasting effects on RGC protection, compared with SC/IVT treatment. In addition, their effects on primary and secondary degeneration, and axonal regeneration, were also investigated, by histology, whole retinal counting, and modelling of RGC loss. SC/DONS was found to significantly reduce RGC apoptosis in vivo and significantly increase RGC survival by targeting secondary rather than primary degeneration. Both SC/DONS and SC/IVT were found to promote RGC axonal regrowth after optic nerve injury, with evidence of GAP-43 expression in RGC somas and axons. SC/DONS may have the potential in the treatment of optic neuropathies, such as glaucoma. We show that SC transplantation can be monitored in real time and that the protective effects of SCs are associated with targeting secondary degeneration, with implications for translating cell-based therapies to the clinic.
Highlights
Partial optic nerve transection represents a reliable and reproducible model for studying secondary degeneration, in which a primary lesion is only made to dorsal axons and leaves those in ventral optic nerve (ON) intact but vulnerable to secondary degeneration.[4,7] Secondary degeneration is thought to be initiated by a cascade of reactive metabolic events, including glutamate excitotoxicity, Ca2+ overload, excess free radical formation, oxidative stress, mitochondrial dysfunction, and increased proteoglycan expression, leading to cell death.[7,8,9,10,11,12,13,14]
Compared with baseline (Figures 2a and b), untreated Partial optic nerve transection (pONT) induced a significant increase in retinal ganglion cell (RGC) apoptosis at both 7 (Figure 2c, maximal level) and 21 (Figure 2d) days (Figure 2g, Po0.01), which was similar to our previous study.[29]
SCs directly to the ON sheath (SC/DONS) significantly reduced RGC apoptosis at both 7 (Figures 2e, g–h, Po0.01) and 21 (Figures 2f, g–h, Po0.05) days compared with untreated pONT
Summary
Partial optic nerve transection (pONT) represents a reliable and reproducible model for studying secondary degeneration, in which a primary lesion is only made to dorsal axons and leaves those in ventral optic nerve (ON) intact but vulnerable to secondary degeneration.[4,7] Secondary degeneration is thought to be initiated by a cascade of reactive metabolic events, including glutamate excitotoxicity, Ca2+ overload, excess free radical formation, oxidative stress, mitochondrial dysfunction, and increased proteoglycan expression, leading to cell death.[7,8,9,10,11,12,13,14]. Activated astrocytes are reported to be a major contributor to spreading and acceleration of secondary degeneration.[8,9]. As in most CNS pathways, the mature ON possesses only a limited ability to repair itself after injury, resulting in permanent vision loss due to the death of retinal ganglion cells (RGCs), the retinal output neurons that transmit visual information to the brain.[15] Compared with the CNS, the PNS has a remarkable ability to regrow after injury, a process in which Schwann cells (SCs) are thought to have a key role.[16,17]. We have recently demonstrated that the highly efficient response of SCs to PN injury is triggered by Ephrin-B/ EphB2 signalling in fibroblasts, which guide SC sorting and migration during nerve repair.[21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
