Transplantation of fibroblasts that overexpress matrix metalloproteinase-3 into the site of spinal cord injury in rats

Growth-inhibitory chondroitin sulfate proteoglycans (CSPGs) are upregulated during glial scar formation at the site of spinal cord injury (SCI) in adult mammals. This CSPG-containing glial scar inhibits axonal regeneration. Matrix metalloproteinases (MMPs) can degrade CSPGs and other inhibitory proteins to promote neurite outgrowth. Increased MMP synthesis and secretion are observed in fibroblasts adjacent to tumor cells that express the protein EMMPRIN (Extracellular Matrix MetalloPRoteinase INducer). EMMPRIN transduction of cells provides an avenue to deliver increased levels of MMPs to the site of SCI in a sustained, localized, and moderate fashion. We explored the use of EMMPRIN-transduced cells as a mechanism to degrade CSPGs, facilitate axonal growth and improve recovery after SCI. Human dermal fibroblasts infected with a recombinant EMMPRIN adenovirus significantly increased secretion of MMP-3 compared to fibroblasts infected with a control adenovirus. Decreased CSPG immunoreactivity was observed in injured spinal cord sections when they were incubated with media from EMMPRIN-transduced fibroblasts. Conditioned media from EMMPRIN-transduced fibroblasts increased the length of neurites that were grown on a CSPG substrate. Rats that received contusive SCI and EMMPRIN-transduced fibroblast transplants demonstrated improved locomotor recovery compared to rats that received control fibroblasts, but not compared to other control groups. EMMPRIN-transplanted rats showed a significant increase in the number of retrogradely labeled cell bodies within brainstem nuclei and an increase in serotonergic fibers distal to the site of injury. EMMPRIN, and consequently MMP, delivery to the injured spinal cord may prove to be beneficial in reducing some of the physical barriers to axonal growth after SCI.