Manipulating the Neuregulin1/ErbB system in peripheral nerves: an in vitro and in vivo laboratory investigation

Peripheral nerve trauma or injuries may lead to sensory or motor function deficits if not properly treated. For this reason, in the last years nerve repair surgical techniques and the regenerative properties of the peripheral nervous system were the focus of many studies. With the aim of improving peripheral nerve regeneration, surgical approaches have matched with new biomedical strategies such as production of new devices and induction of specific factors to enhance the endogenous mechanisms of recovery. The Neuregulin/ErbB system plays an important role in peripheral nervous system both in normal and pathological conditions. In our study we explored the possibility to manipulate the system, in vitro and in vivo, in order to increase Schwann cell migration and thus improve injured peripheral nerve regeneration. To interfere with the Neuregulin1/ErbB system soluble ecto-ErbB4, a protein fragment endogenously released by cells expressing the cleavable isoform of the NRG1 receptor ErbB4, was expressed in vitro in Neuregulin1 expressing glial cells. A strong increase in cell motility was observed. Experiments suggest that activation of a back signaling, mediated by the transmembrane Neuregulin1 isoform, plays a crucial role in the migratory activity induced by fragment expression. Nevertheless, in vivo manipulation of the Neuregiln1/ErbB system through local delivery of soluble ecto-ErbB4 by gene transfer in the muscle-vein-combined nerve guide, did not result in strong motor functional recovery or improved nerve fiber regeneration. These results indicate that ecto-ErbB4 could be used in vivo as a tool to manipulate the Neuregulin1/ErbB system, but further studies are required to design an effective delivery strategy for an in vivo Neuregulin1/ErbB system manipulation, that can strongly promote post-traumatic peripheral nerve regeneration.