Abstract
Neurotrophic factors (NTF) secreted by Schwann cells in a sciatic nerve (SN) graft promote retinal ganglion cell (RGC) axon regeneration after either transplantation into the vitreous body of the eye or anastomosis to the distal stump of a transected optic nerve. In this study, we investigated the neuroprotective and growth stimulatory properties of SN grafts in which Schwann cells had been killed (acellular SN grafts, ASN) or remained intact (cellular SN grafts, CSN). We report that both intravitreal (ivit) implanted and optic nerve anastomosed CSN promote RGC survival and when simultaneously placed in both sites, they exert additive RGC neuroprotection. CSN and ASN were rich in myelin-associated glycoprotein (MAG) and axon growth-inhibitory ligand common to both the central nervous system (CNS) and peripheral nervous system (PNS) myelin. The penetration of the few RGC axons regenerating into an ASN at an optic nerve transection (ONT) site is limited into the proximal perilesion area, but is increased >2-fold after ivit CSN implantation and increased 5-fold into a CSN optic nerve graft after ivit CSN implantation, potentiated by growth disinhibition through the regulated intramembranous proteolysis (RIP) of p75NTR (the signalling trans-membrane moiety of the nogo-66 trimeric receptor that binds MAG and associated suppression of RhoGTP). Mϋller cells/astrocytes become reactive after all treatments and maximally after simultaneous ivit and optic nerve CSN/ASN grafting. We conclude that simultaneous ivit CSN plus optic nerve CSN support promotes significant RGC survival and axon regeneration into CSN optic nerve grafts, despite being rich in axon growth inhibitory molecules. RGC axon regeneration is probably facilitated through RIP of p75NTR, which blinds axons to myelin-derived axon growth-inhibitory ligands present in optic nerve grafts.
Highlights
Axons readily regrow in the damaged peripheral nervous system (PNS) but fail to do so in the injured central nervous system (CNS)
(ii), After optic nerve grafting: Only 13% Retinal Ganglion Cell (RGC) survived in the ivitS /ONTASN group, not significantly different from CON/ivitS /optic nerve transection (ONT) group values, significant RGC neuroprotection of 15% was recorded in the ivitS /ONTCSN group. (iii) After both ivit and optic nerve grafting: The greatest
RGC neuroprotection of ~58% was achieved in the ivitCSN /ONTCSN group, i.e., >50% RGC survival compared to the numbers of RGC surviving after ivitCSN /ONT (25%) and ivitS /ONTCSN (15%), suggesting that combined ivitCSN /ONTCSN grafting had a synergistic effect on RGC survival
Summary
Axons readily regrow in the damaged peripheral nervous system (PNS) but fail to do so in the injured central nervous system (CNS) This differential injury response is attributed to the presence inAxons readily regr injured central nervous the PNS of neurotrophic factors (NTFs) derived from Schwann cells [1,2,3] and the growth compatible in the PNS of neurotr substrate of their laminin-rich basal lamina tubes and, in the injured CNS, to a lack of NTF support substrate of and the presence of axon growth-inhibitory ligands. The possibility that Schwann cell basal lamina tube laminin may override the Article growth inhibitory activity of MAG and both Schwann cell-derived matrix metalloprotease (MMP)-2 degradation of PNS inhibitors [14] and NTF-induced activation of the PI3K/Akt pathway [15,16,17,18]
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