GDNF preconditioning can overcome Schwann cell phenotypic memory.

While it is known that Schwann cells (SCs) provide cues to enhance regeneration following peripheral nerve injury, the effect of SC phenotypic memory (muscle or cutaneous nerve-derived) on enhancing axonal regeneration and functional recovery has been unclear in the literature. In particular, differences between muscle and cutaneous nerve-derived SC may encourage specific motor or sensory axonal guidance in cell/tissue transplantation therapies. Thus, the goal of this study was to determine whether phenotypically matched combinations of neurons and SCs stimulate greater axonal extension compared to mismatched combinations (i.e. motor neurons/muscle nerve-derived SCs vs. motor neurons/cutaneous nerve-derived SCs). Additionally, the effect of glial cell line-derived neurotrophic factor (GDNF) treatment on SC-neuron interaction was also evaluated. In order to examine these interactions, microfluidic devices were used to assess the effects of soluble factors secreted from SCs on neurons. Unlike traditional co-culture methods, the devices allow for easier quantification of single neurite extension over long periods of time, as well as easy cell and media sampling of pure populations for biochemical analyses. Results demonstrated longer neurite growth when neurons are cultured with phenotype matched SCs, suggesting that SCs are capable of retaining phenotypic memory despite a prolonged absence of axonal contact. Furthermore, the negative effect of mismatched cultures can be overcome when mismatched SCs are preconditioned with GDNF. These results suggest that treatment of SCs with GDNF could enhance their ability to promote regeneration through mismatched grafts frequently used in clinical settings.