Abstract:

Spinal cord injury (SCI) is a traumatic event that can lead to permanent motor and sensory deficits. After the initial trauma, axons of surviving neurons rapidly retract. While there may be a small degree of abortive sprouting, virtually all attempts at robust regrowth across the lesion site ultimately fail. Thus, neurons below the level of the injury are permanently disconnected from their normal input, resulting in persistent loss of function.  Recently, several labs have begun to elucidate what factors may mediate the intrinsic, growth deficiency in mature CNS neurons. Interestingly, increasing levels of several developmentally-regulated transcription factors, such as several members of the Krüppel-like factor (KLF) family and Sox11, in adult neurons improves their ability to re-grow or sprout. Elegant work by Zhigang He and colleagues showed that the tumor suppressor PTEN (phosphatase and tensin homolog), is upregulated in mature neurons. PTEN inhibits the activation of the protein synthesis regulator mTOR (mammalian target of rapamycin). MTOR activation increases the synthesis of proteins that are associated with growth and survival. Moreover, genetic deletion of PTEN increases mTOR activation and results in substantial axon growth after injury. However, while this approach addresses the intrinsic limitations to growth after injury, the inhibitory barriers within the glial scar remain intact. Recently, we hypothesized that simultaneously addressing intrinsic neuronal deficits in axon regrowth and extrinsic, scar-associated impediments to regeneration would result in significant regeneration after SCI. We grafted PN into the complete, thoracic level SCI to provide a growth-promoting environment to span the cavity. We injected adeno-associated virus (AAV) encoding for green fluorescent protein (GFP; control vector) or constitutively active Rheb (caRheb; Ras homolog enriched in brain) rostral to the lesion to transduce and drive mTOR activation in neurons above the SCI. Lastly, we treated the distal graft-host interface with ch’ase to diminish the effects of the inhibitory extracellular matrix in the glial scar. Because multiple facets will need to be considered to achieve functional repair of the SCI, combinatorial strategies focused on manipulate intrinsic neuronal growth potential while simultaneously reducing the extrinsic inhibitors of axon extension will likely be a staple for future therapies in SCI.