Neuronal substrates alter the migratory responses of nonmyelinating Schwann cells to controlled brain-derived neurotrophic factor gradients.

Abstract

Neurodegeneration and dysfunction cause mobility impairment and/or paralysis in millions of adults, worldwide. Motor deficit and recovery in adults depend upon the plasticity of the neuromuscular junction (NMJ), a tripartite, biochemical synapse that transduces electrical impulses from the brain into voluntary contraction of skeletal muscle. Nonmyelinating Schwann cells (nmSCs) of the NMJ have been increasingly recognized as active synaptic partners with motor neurons and muscle and have become recent therapeutic targets for regeneration. nmSC synaptic transmission, plasticity, and growth are strongly modulated by brain-derived neurotrophic factor (BDNF), whose regenerative abilities have been explored through emerging biomaterials and tissue-engineered systems, as well as via clinical trials. Experimental models engineered to investigate integrated NMJ response(s) to local gradients of BDNF will both advance our understanding of key modulators of synaptic activity, postinjury, and aid in the development of NMJ-targeted, regenerative therapies to restore mobility. The current study examined the ability of nmSCs to respond to microfluidically controlled BDNF signaling upon different haptotactic substrates of motor neurons (MNs) and laminin adhesion coating. Tests seeding nmSCs sequentially with MNs illustrated that sequential seeding reported a fivefold increase in levels of tropomyosin receptor kinase B expression in response to BDNF signaling and a nearly fivefold increase in migration distance along BDNF gradients. By contrast, concurrent seeding of MNs and nmSCs upon laminin adhesion coating illustrated a difference in migration distance of less than one third-fold over control. Our findings are among the first to examine migratory responses of nmSCs for regenerative strategies and highlight the potential to restabilize NMJ synaptic activity by affecting nmSC behaviors through therapeutic BDNF and seeding with MNs.