GDNF pretreatment overcomes Schwann cell phenotype mismatch to promote motor axon regeneration via sensory graft

Abstract

In the clinic, severe motor nerve injury is commonly repaired by autologous sensory nerve bridging, but the ability of Schwann cells (SCs) in sensory nerves to support motor neuron axon growth is poor due to phenotype mismatch. In vitro experiments have demonstrated that sensory-derived SCs overcome phenotypic mismatch-induced growth inhibition after pretreatment with exogenous glial cell-derived neurotrophic factor (GDNF) and induce motor neuron axonal growth. Thus, we introduced a novel staging surgery: In the first stage of surgery, the denervated sensory nerve was pretreated with sustained-release GDNF, which was encapsulated into a self-assembling peptide nanofiber scaffold (SAPNS) RADA-16I in the donor area in vivo. In the second stage of surgery, the pretreated sensory grafts were transplanted to repair motor nerve injury. Motor axon regeneration and remyelination and muscle functional recovery after the second surgery was compared to those in the control groups. The expression of genes previously shown to be differently expressed in motor and sensory SCs was also analyzed in pretreated sensory grafts by qRT-PCR to explore possible changes after exogenous GDNF application. Exogenous GDNF acted directly on the denervated sensory nerve graft in vivo, increasing the expression of endogenous GDNF and sensory SC-derived marker brain-derived neurotrophic factor (BDNF). After transplantation to repair motor nerve injury, exogenous GDNF pretreatment promoted the regeneration and remyelination of proximal motor axons and the recovery of muscle function. Further research into how phenotype, gene expression and changes in neurotrophic factors in SCs are affected by GDNF will help us design more effective methods to treat peripheral nerve injury.