Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration

Abstract

Peripheral nerve injury (PNI), one of the most common concerns following trauma, can result in a significant loss of sensory or motor function. Restoration of the injured nerves requires a complex cellular and molecular response to rebuild the functional axons so that they can accurately connect with their original targets. However, there is no optimized therapy for complete recovery after PNI. Supplementation with exogenous growth factors (GFs) is an emerging and versatile therapeutic strategy for promoting nerve regeneration and functional recovery. GFs activate the downstream targets of various signaling cascades through binding with their corresponding receptors to exert their multiple effects on neurorestoration and tissue regeneration. However, the simple administration of GFs is insufficient for reconstructing PNI due to their short half‑life and rapid deactivation in body fluids. To overcome these shortcomings, several nerve conduits derived from biological tissue or synthetic materials have been developed. Their good biocompatibility and biofunctionality made them a suitable vehicle for the delivery of multiple GFs to support peripheral nerve regeneration. After repairing nerve defects, the controlled release of GFs from the conduit structures is able to continuously improve axonal regeneration and functional outcome. Thus, therapies with growth factor (GF) delivery systems have received increasing attention in recent years. Here, we mainly review the therapeutic capacity of GFs and their incorporation into nerve guides for repairing PNI. In addition, the possible receptors and signaling mechanisms of the GF family exerting their biological effects are also emphasized.

Keywords: axonal regeneration; basic fibroblast growth factor; growth factors; nerve conduits; nerve growth factor; peripheral nerve injury; signaling cascade.

Fig. 1. Schematic diagram illustrating the process of degeneration and regeneration after PNI.

When normal nerves (a) suffer from physical injury, the portion of the lesion site and its distal stump undergo destruction and breakdown and produce myelin debris. This degenerative process is called WD (b). Then, SCs recruit macrophages to scavenge degenerated myelin fragments (c). Meanwhile, SCs proliferate and migrate alone the basal lamina to form bands of Büngner, which guides axon to reinnervate towards the corresponding target (d).

Fig. 2. Schematic representation of the typical GF signaling cascade and its main downstream effectors.

When GF ligands are bound to their corresponding membrane spanning receptors (TrkA, TrkB, TrkC, P75^NTR), they become phosphorylated and interact with other adaptor proteins, such as FRS2, Grb2, Gab1, She, Grb2, or Sos, to form one of various arrangements of multiprotein complexes that localize to the cell membrane and activate downstream signaling cascades, including PI3K/Akt, MAPK/ERK, JNK/c-Jun, and Rho A/ROCK. These cascade activation events are implicated in axonal outgrowth or regeneration, SC plasticity, remyelination, microtubule stability and neuronal survival following nerve injury.

Fig. 3. Other signaling cascades that involve GFs controlling PNI repair.

Some GFs, such as FGF10, BDNF, NT-3 and FGF-2, coordinately activate the Nrg1/ErbB, JAK/ STAT 3, or PLCg/Ca²⁺Oct6 pathways to initiate neuronal development, axonal remodeling, SC differentiation and remyelination.