Secretion of EGF-like domain of heregulinβ promotes axonal growth and functional recovery of injured sciatic nerve.

Neuregulin 1 (NRG1) and epidermal growth factor receptor (ErbB) signaling pathways control Schwann cells during axonal regeneration in an injured peripheral nervous system. We investigated whether a persistent supply of recombinant NRG1 to the injury site could improve axonal growth and recovery of sensory and motor functions in rats during nerve regeneration. We generated a recombinant adenovirus expressing a secreted form of EGF-like domain from Heregulinβ (sHRGβE-Ad). This virus, sHRGβE-Ad allowed for the secretion of 30-50 ng of small sHRGβE peptides per 10(7-8) virus particle outside cells and was able to phosphorylate ErbB receptors. Transduction of the concentrated sHRGβE-Ad into an axotomy model of sciatic nerve damage caused an effective promotion of nerve regeneration, as shown by histological features of the axons and Schwann cells, as well as increased expression of neurofilaments, GAP43 and S100 in the distal stump of the injury site. This result is consistent with longer axon lengths and thicker calibers observed in the sHRGβE-Ad treated animals. Furthermore, sensory and motor functions were significantly improved in sHRGβE-Ad treated animals when evaluated by a behavioral test. These results suggest a therapeutic potential for sHRGβE-Ad in treatment of peripheral nerve injury.