A Molecule Family Hinders Spinal Cord Regeneration, UF Brain Institute Team Finds

November 22, 1999

GAINESVILLE—Nerve tissue transplants are among the promising experimental therapies to restore communication among cells in injured spinal cords, but scientists long have wondered why the transplanted cells don’t grow more vigorously, thereby enhancing the level of recovery.

Now experiments in rats at the University of Florida Brain Institute suggest a possible explanation and a potential target for therapeutic intervention: Researchers suspect that in the days following a transplant, a particular family of molecules forms a barrier that prevents many nerve fiber connections from growing.

The molecules, chondroitin sulfate proteoglycans, or CSPGs, consist of a protein core surrounded by sugars arranged like bristles on a bottle brush; they occur naturally throughout the body. During development, CSPGs are thought to play a vital role by forming boundaries that guide migrating cells to appropriate destinations.

But following an injury, their levels increase so substantially that their growth-regulating function appears to contribute to a failure of the nerve cells to regenerate, according to research published in this month’s issue of the journal Experimental Neurology.

The new study expands on previous research indicating increased levels of CSPGs following head and spinal cord injury. Unlike earlier research, however, the UF experiments involved animals with compression-type injuries, which are considered to closely mimic the damage typically experienced by people.

The UF experiments also were the first to look at CSPG expression in cellular transplants.

“We were very surprised to see that the CSPGs increased rapidly, not only in the host around the transplant, but in the transplanted tissue itself,” said Dena R. Howland, a research assistant professor of neuroscience in UF’s College of medicine and one of the paper’s authors. “This increase appears to create a wall of molecules known to be associated with limiting growth. Perhaps as injured host fibers are trying to grow into the transplant, they are blocked by this wall of CSPGs. And, as the fibers of transplanted neurons are trying to grow out, they are also rapidly blocked.”

“These molecules may be one of factors that contribute to the failure of the adult, mammalian injured spinal cord to regenerate,” added Michele L. Lemons, a visiting assistant professor at Hamilton College in New York who conducted the experiments while a UF doctoral student in neuroscience. “Therefore, a better understanding of these molecules could significantly contribute to our understanding of regeneration failure.”

Continuing research at UF will explore which individual molecules within the class of CSPGs limit nerve cell growth.

UF scientists, with support from the U.S. National Institutes of Health, the U.S. Department of Veterans Affairs and the state of Florida, have been exploring multidisciplinary approaches to the treatment of spinal cord injury for more than a decade. Building upon findings earlier in the 1990s that they could restore some lost physical functions in spinal cord-injured laboratory animals, they have continued to develop animal injury and treatment models.

Those efforts have been enhanced in recent weeks now that the UF Brain Institute – a collaborative campuswide organization with more than 280 affiliated researchers — is home to the world’s most powerful magnetic resonance imaging system for animals up to the size of 18-pound primates.

In 1997, UF began a small trial testing the feasibility of embryonic nerve tissue transplants in humans for spinal cord injury. While it is too early for results from that study, the work speaks to a potential for regeneration that only recently seemed like a pipe dream.

“Up until 20 years ago, it was thought that spinal cord neurons simply did not have the capacity to regenerate,” noted Douglas Anderson, chairman of UF’s neuroscience department and a career research scientist with the Malcom Randall Veterans Affairs Medical Center in Gainesville. “But once it was demonstrated that they could grow in the appropriate terrain, the hunt has been on to make that happen.”