TY - JOUR T1 - Metalloproteinase-Dependent Predegeneration <em>In Vitro</em> Enhances Axonal Regeneration within Acellular Peripheral Nerve Grafts JF - The Journal of Neuroscience JO - J. Neurosci. SP - 10408 LP - 10415 DO - 10.1523/JNEUROSCI.22-23-10408.2002 VL - 22 IS - 23 AU - Craig A. Krekoski AU - Debbie Neubauer AU - James B. Graham AU - David Muir Y1 - 2002/12/01 UR - http://www.jneurosci.org/content/22/23/10408.abstract N2 - Injury to peripheral nerve initiates a degenerative process that converts the denervated nerve from a suppressive environment to one that promotes axonal regeneration. We investigated the role of matrix metalloproteinases (MMPs) in this degenerative process and whether effective predegenerated nerve grafts could be producedin vitro. Rat peripheral nerve explants were cultured for 1–7 d in various media, and their neurite-promoting activity was assessed by cryoculture assay, in which neurons are grown directly on nerve sections. The neurite-promoting activity of cultured nerves increased rapidly and, compared with uncultured nerve, a maximum increase of 72% resulted by 2 d of culture in the presence of serum. Remarkably, the neurite-promoting activity of short-term cultured nerves was also significantly better than nerves degeneratedin vivo. We examined whether in vitrodegeneration is MMP dependent and found that the MMP inhibitorN-[(2R)-2(hydroxamidocarbonylmethyl)-4-methylpantanoyl]-l-tryptophan methylamide primarily blocked the degenerative increase in neurite-promoting activity. In the absence of hematogenic macrophages, MMP-9 was trivial, whereas elevated MMP-2 expression and activation paralleled the increase in neurite-promoting activity. MMP-2 immunoreactivity localized to Schwann cells and the endoneurium and colocalized with gelatinolytic activity as demonstrated by in situ zymography. Finally,in vitro predegenerated nerves were tested as acellular grafts and, compared with normal acellular nerve grafts, axonal ingressin vivo was approximately doubled. We conclude that Schwann cell expression of MMP-2 plays a principal role in the degenerative process that enhances the regeneration-promoting properties of denervated nerve. Combined with their low immunogenicity, acellular nerve grafts activated by in vitropredegeneration may be a significant advancement for clinical nerve allografting. ER -