Peptide amphiphile (PA) molecules that self-assemble in vivo into supramolecular nanofibers were used as a therapy in a mouse model of spinal cord injury (SCI). Because self-assembly of these molecules is triggered by the ionic strength of the in vivo environment, nanoscale structures can be created within the extracellular spaces of the spinal cord by simply injecting a liquid. The molecules are designed to form cylindrical nanofibers that display to cells in the spinal cord the laminin epitope IKVAV at nearly van der Waals density. IKVAV PA nanofibers are known to inhibit glial differentiation of cultured neural stem cells and to promote neurite outgrowth from cultured neurons. In this work, in vivo treatment with the PA after SCI reduced astrogliosis, reduced cell death, and increased the number of oligodendroglia at the site of injury. Furthermore, the nanofibers promoted regeneration of both descending motor fibers and ascending sensory fibers through the lesion site. Treatment with the PA also resulted in significant behavioral improvement. These observations demonstrate that it is possible to inhibit glial scar formation and to facilitate regeneration after SCI using bioactive three-dimensional nanostructures displaying high densities of neuroactive epitopes on their surfaces.

Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that serves to repair damaged blood brain barrier and a subsequent hyperplastic response that results in a dense scar that impedes axon regeneration. The mechanisms regulating these two phases of astrogliosis are beginning to be elucidated. In this study, we found that microRNA-21 (miR-21) increases in a time-dependent manner following SCI in mouse. Astrocytes adjacent to the lesion area express high levels of miR-21 whereas astrocytes in uninjured spinal cord express low levels of miR-21. To study the role of miR-21 in astrocytes after SCI, transgenic mice were generated that conditionally over-express either the primary miR-21 transcript in astrocytes or a miRNA sponge designed to inhibit miR-21 function. Over-expression of miR-21 in astrocytes attenuated the hypertrophic response to SCI. Conversely, expression of the miR-21 sponge augmented the hypertrophic phenotype, even in chronic stages of SCI recovery when astrocytes have normally become smaller in size with fine processes. Inhibition of miR-21 function in astrocytes also resulted in increased axon density within the lesion site. These findings demonstrate a novel role for miR-21 in regulating astrocytic hypertrophy and glial scar progression after SCI, and suggest miR-21 as a potential therapeutic target for manipulating gliosis and enhancing functional outcome.

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Stem cell therapy is a potential treatment for spinal cord injury (SCI), and a variety of different stem cell types have been evaluated in animal models and humans with SCI. No consensus exists regarding the type of stem cell, if any, that will prove to be effective therapeutically. Most data suggest that no single therapy will be sufficient to overcome all the biological complications caused by SCI. Rationales for therapeutic use of stem cells for SCI include replacement of damaged neurons and glial cells, secretion of trophic factors, regulation of gliosis and scar formation, prevention of cyst formation, and enhancement of axon elongation. Most therapeutic approaches that use stem cells involve implantation of these cells into the spinal cord. The attendant risks of stem cell therapy for SCI—including tumor formation, or abnormal circuit formation leading to dysfunction—must be weighed against the potential benefits of this approach. This Review will examine the biological effects of SCI, the opportunities for stem cell treatment, and the types of stem cells that might be used therapeutically. The limited information available on the possible benefits of stem cell therapy to humans will also be discussed.