The cellular and molecular basis of peripheral nerve regeneration

Abstract

Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regenerations may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.

Persistence of tracer in the application site?a potential confounding factor in nerve regeneration studies

“…This indicated that axons distal to the suture remain capable of transporting tracers for a short time and that the dye may cross the suture and reach the DRG provided that the distal nerve remains in contact with its proximal stump. This is in accordance with previous reports, which described retrograde transport (Nitta et al, 1999) and excitability (Fu and Gordon, 1997) in the distal part of sectioned axons for a short period after transection. To avoid this "crossing" phenomenon, we waited three days after the nerve lesion and repair before we applied the tracers.…”

On the use of fast blue, fluoro-gold and diamidino yellow for retrograde tracing after peripheral nerve injury: uptake, fading, dye interactions, and toxicity

“…These varying results may to some extent be due to counting problems, but also to age, postoperative survival time, and proximity of lesion (see Lowrie and Vrbová, 1992;Snider et al, 1992;Fu and Gordon, 1997). By analogy to findings in the DRGs (Ygge and Aldskogius, 1984;Arvidsson et al, 1986;Groves et al, 1997), an increased amount of neuronal disappearence in the motor columns could take place if very long survival times were studied.…”

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…Nerve transection triggers a set of changes in the nerve stump distal to the injury that are collectively referred to as Wallerian degeneration (reviewed in Chen et al, 2007;Fu and Gordon, 1997;Raivich and Makwana, 2007;Scherer and Salzer, 2001;Stoll et al, 2002;Vargas and Barres, 2007). The major events are: axon death, invasion of blood-borne macrophages, collapse of myelin sheaths together with ingestion and breakdown of the myelin material, a transient phase of Schwann cell proliferation, and a reversal of molecular expression from that characteristic of mature myelinating and nonmyelinating cells back to one that resembles the immature state.…”