An “Attractive” Approach for Repairing CNS Injury

Our able-bodied lives hang by a thread. Severed axons do not regenerate following damage to the brain or the spinal cord, because their regrowth is blocked in part by a glial scar that forms a barrier both physical and chemical. To bridge that glial scar, the Pharmacology laboratory of Sally Meiners at the UMDNJ-Robert Wood Johnson Medical School in New Jersey is designing grafts or scaffolds that incorporate small molecules from the extracellular matrix (ECM) to coax axons back across the gap and onto fertile ground for regrowth.

Here Meiners reports preliminary success with one such molecule, a 15 amino acid peptide called C3 found in human tenascin-C (a type of protein known as "fnC" ). Interestingly, tenascin-C is an ECM protein that helps "wire up" the developing central nervous system (CNS) early in life. In Meiners's experiments, the C3 peptide gave directional clues to the growing ends ('neurites') of rat neurons cultured in dishes. Given a choice, neurites preferentially crossed onto substrates coated with C3, a process she defines as "neurite attraction." Intriguingly, neurites crossed onto C3 even in the presence of chondroitin sulfate proteoglycans, a major class of inhibitory molecules present in glial scars. Thus, adding C3 to grafts might help regrowing axons enter scar tissue in brain or spinal cord lesions.

However, the C3 peptide also had an undesirable trait: the neurites growing on C3 substrates did not want to leave. This was bad news for potential CNS grafts, since axons must not only enter the graft at the near end of the lesion, they must also exit the graft at the far end to reach their targets. To see if she could 'fine tune' C3's activity, Meiners modified its amino acid sequence. She came up with three synthetic versions: one that attracted and retained neurites, a second version that retained but did not attract them, and a third that attracted but did not retain them.

"Since the 'exit phase' is a major concern with CNS grafts," says Meiners, "these results suggest it will be possible to design grafts in which 'attractive' fnC-derived peptides with minimal retention activity entice axons to migrate across the glial scar. This would facilitate guided axonal regrowth following CNS injury." She acknowledges that this in vitro work is still a long way from actually regrowing severed axons in CNS patients. To bridge this gap, her laboratory is now testing these ideas in an in vivo model of spinal cord injury.

Neurite Attraction and Neurite Retention are Mediated by Distinct Sites in the FnC Domain of Human Tenascin, -C H. Liu, 1 M. Schachner, 2 S. A. Meiners1; 1 Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, 2 Zentrum fur Molekulare Neurobiologie, Universitaet Hamburg, Hamburg, Germany

At the ASCB Meeting: Session 174, Minisymposium 5: ECM Biogenesis & Function, Room 147A/B. Author presents: Sunday, Dec. 5, 3:40 — 5:45 PM.