Combinatorial therapy elicits spinal cord regeneration more than a year after injury

October 28, 2009

New research finds that adult neurons can still regenerate as long as 15 months after a spinal cord injury. The study, published by Cell Press in the October 29th issue of the journal Neuron, highlights the success of a strategy that targets multiple environmental and intrinsic obstacles known to limit nervous system plasticity and regeneration.

"Despite advances in promoting axonal regeneration after acute spinal cord injury, elicitation of regeneration of key neuronal processes, called axons, after chronic spinal cord injury remains a formidable challenge," explains senior study author Dr. Mark H. Tuszynski from the University of California, San Diego. "In fact, few studies have examined axonal regeneration when therapies are administered at delays greater than 8 weeks after injury."

Dr. Tuszynski and colleagues examined the capacity of axons to regenerate when experimental therapies were provided after exceptionally prolonged delays in adult rats with injuries to the upper part of the spinal cord. The researchers focused on the dorsal column sensory tract because it has a projection that is anatomically well-defined and normally fails to regenerate after injury.

Both the intrinsic growth state of the neurons projecting to the lesion site and the surrounding inhibitory environment were modified. Specifically, neuron-intrinsic regeneration-associated gene expression was upregulated, bone marrow stromal cells were grafted to the lesion site, and a key neurotrophic factor was expressed in the dorsal column at time points ranging from 6 weeks to 15 months after injury.

The combination of delayed therapies induced activation of transcription factors and regeneration-associated genes that are normally seen with acute injury. This suggests recruitment of critical intrinsic molecular mechanisms that promote axon regeneration. Further, the researchers confirmed regeneration of axons beyond the lesion site. Importantly, examination of control animals revealed that modification of intrinsic growth state alone, or the environment alone, was insufficient to support axonal regrowth beyond the site of injury.

"Our results demonstrate that axonal regeneration in the adult central nervous system could be induced at unprecedented post-injury time points when experimental treatments modified the intrinsic growth state of the neurons and the nonpermissive injury environment," says Dr. Tuszynski. "The ultimate goal is to provide rational, safe therapies that may improve the quality of life of humans with devastating spinal cord injuries." The first author of the study was Dr. Ken Kadoya, also of the University of California, San Diego. The work was supported by the National Institutes of Health and the Veteran's Administration.
The researchers include Ken Kadoya, University of California, San Diego, La Jolla, CA; Shingo Tsukada, University of California, San Diego, La Jolla, CA; Paul Lu, University of California, San Diego, La Jolla, CA, Veterans Affairs Medical Center, San Diego, CA; Giovanni Coppola, University of California, Los Angeles, Los Angeles, CA; Dan Geschwind, University of California, Los Angeles, Los Angeles, CA; Marie T. Filbin, Hunter College, New York, NY; Armin Blesch, University of California, San Diego, La Jolla, CA; and Mark H. Tuszynski, University of California, San Diego, La Jolla, CA, Veterans Affairs Medical Center, San Diego, CA.

Cell Press

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