Lentiviral-mediated expression of polysialic acid in spinal cord and conditioning lesion promote regeneration of sensory axons into spinal cord

Abstract

In adult mammals, sensory axons that regenerate in the dorsal root are unable to grow across the dorsal root entry zone (DREZ) into the spinal cord. In this study we examined whether, by inducing expression of polysialic acid (PSA) (a large carbohydrate attached to molecules on the cell surface), in the spinal cord by lentiviral vector (LV) delivery of polysialyltransferase (PST), DREZ could be rendered permeable to regenerating sensory axons. High-level PSA expression was observed in astrocytes and many other cell types after LV/PST injection into the spinal cord. In animals receiving LV/PST injection in combination with a conditioning lesion, many axons penetrated the DREZ following L4-5 dorsal rhizotomy. Some axons reached lamina IV/V and extended rostrally and caudally in the degenerating dorsal column. In LV/green fluorescent protein (GFP)-injected animals, most of the regenerating axons were halted before DREZ, even with a conditioning lesion. More Schwann cells migrated into the LV/PST-transduced spinal cord, many of them accompanying the regenerating axons. A Schwann cell-astrocyte-dorsal root ganglion (DRG) neuron co-culture experiment confirmed that induced PSA expression on astrocytes facilitates the crossing of DRG axons from Schwann cells to astrocytes. These data suggest that over-expression of PSA can create a favorable condition for regenerating axons, and that this approach could form part of a combinational therapeutic strategy for promoting the repair of central nervous system (CNS) injuries.