Studies on the Development and Behavior of the Dystrophic Growth Cone, the Hallmark of Regeneration Failure, in Anin VitroModel of the Glial Scar and after Spinal Cord Injury

We have developed a novelin vitromodel of the glial scar that mimics the gradient of proteoglycan foundin vivoafter spinal cord injury. In this model, regenerated axons from adult sensory neurons that extended deeply into the gradient developed bulbous, vacuolated endings that looked remarkably similar to dystrophic endings formedin vivo. We demonstrate that despite their highly abnormal appearance and stalled forward progress, dystrophic endings are extremely dynamic bothin vitroandin vivoafter spinal cord injury. Time-lapse movies demonstrated that dystrophic endings continually send out membrane veils and endocytose large membrane vesicles at the leading edge, which were then retrogradely transported to the rear of the “growth cone.” This direction of movement is contrary to membrane dynamics that occur during normal neurite outgrowth. As further evidence of this motility, dystrophic endings endocytosed large amounts of dextran bothin vitroandin vivo. We now have anin vitromodel of the glial scar that may serve as a potent tool for developing and screening potential treatments to help promote regeneration past the lesionin vivo.