Abstract
We have demonstrated that overcoming matrix metalloproteinase (MMP)-mediated suppression of glial proliferation stimulates axonal regeneration in the peripheral nervous system. The regenerative capacity of the adult CNS in response to injury and demyelination depends on the ability of multipotent glial NG2+ progenitor cells to proliferate and mature, mainly into oligodendrocytes. Herein, we have established the important role of MMPs, specifically MMP-9, in regulation of NG2+ cell proliferation in injured spinal cord. Targeting transiently induced MMP-9 using acute MMP-9/2 inhibitor (SB-3CT) therapy for two days after T9-10 spinal cord dorsal hemisection produced a significant increase in mitosis (assessed by bromodeoxyuridine incorporation) of NG2+ cells but not GFAP+astrocytes and Iba-1+ microglia and/or macrophages. Acute MMP-9/2 blockade reduced the shedding of the NG2 proteoglycan and of the NR1 subunit of the N-methyl D-aspartate (NMDA) receptor, whose decline is believed to accompany NG2+ cell maturation into OLs. Increase in post-mitotic oligodendrocytes during remyelination and improved myelin neuropathology in the hemisected spinal cord were accompanied by locomotion and somatosensory recovery after acute MMP-9/2 inhibition. Collectively, these data establish a novel role for MMPs in regulation of NG2+ cell proliferation in the damaged CNS, and a long-term benefit of acute MMP-9 block after SCI.