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Review
. 2019 Jan;14(1):24-33.
doi: 10.4103/1673-5374.243699.

Peripheral nerve regeneration and intraneural revascularization

Martial Caillaud  1 , Laurence Richard  2 , Jean-Michel Vallat  2 , Alexis Desmoulière  1 , Fabrice Billet  1
Affiliations
Review

Peripheral nerve regeneration and intraneural revascularization

Martial Caillaud et al. Neural Regen Res. 2019 Jan.

Abstract

Peripheral nerves are particularly vulnerable to injuries and are involved in numerous pathologies for which specific treatments are lacking. This review summarizes the pathophysiological features of the most common traumatic nerve injury in humans and the different animal models used in nerve regeneration studies. The current knowledge concerning Wallerian degeneration and nerve regrowth is then described. Finally, the involvement of intraneural vascularization in these processes is addressed. As intraneural vascularization has been poorly studied, histological experiments were carried out from rat sciatic nerves damaged by a glycerol injection. The results, taken together with the data from literature, suggest that revascularization plays an important role in peripheral nerve regeneration and must therefore be studied more carefully.

Keywords: Sunderland's classification; Wallerian degeneration; angiogenesis; compression; crush; glycerol; transection; traumatic.

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Conflict of interest statement

None

Figures

Figure 1
Figure 1
Sunderland’s classification of nerve injuries. Grade I: Temporary interruption of myelin sheath without loss of axonal continuity. Grade II: Loss of continuity of the axon and its myelin sheath, the various connective tissues of the nerve (endoneurium, epineurium and perineurium) are preserved). Grade III, IV and V: Partial (III, IV) or total (V) section of the nerve. A distinction is made between grade III (in which the axon and the endoneurium are damaged but not the perineurium), grade IV (in which the axon, the endoneurium and the perineurium are damaged but the epineurium is preserved) and grade V (in which the nerve is transected). Adapted from Menorca et al. (2013).
Figure 2
Figure 2
Schematic representation of Wallerian degeneration and nerve regeneration. At the time of nerve injury (D0), surrounding cells (Schwann cells and endoneurial fibroblasts) are immediately damaged and die by apoptosis. At two days after injury (D2), axons degenerate, notably due to the action of Ca2+ and Na+ release. Concomitantly, neuropeptides released by damaged axons, such as substance P (SP) and calcitonin gene-related peptide (CGRP), induce the swelling of intraneural blood vessels. This vasodilatation, coupled with the release of monocyte chemoattractant protein-1 (MCP-1) by Schwann cells, stimulates recruitment of migrating and resident macrophages. These macrophages phagocytose axonal and myelin debris and release vascular endothelial growth factor (VEGF)-A, leading to the formation of neovessels (D7). At the same time, intact Schwann cells secrete nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF) which stimulate the formation of new Schwann cells. Oxygen and nutrients supplied by neovessels are required for the formation of “bands of Büngner” that then form a physical guide for axonal regrowth (D14). The release of adenosine triphosphate (ATP) and acetylcholine (Ach) by axons allows their self-stimulation (D14–21). Two months after injury, the general appearance of the nerve is almost normal, although some nerve fibers still have a thin sheath of myelin (D60). MAC-2: Galectin-3.
Figure 3
Figure 3
The vascularization of peripheral nerves. Microcirculation of peripheral nerves derives from external vascular system from which emerge radicular branch vessels supplying the internal vascular system. Internal vascular system consists of longitudinally oriented peri-fascicular vessels that pass through epineurium (extraneural vascular system), reach the perineurium and ultimately join the endoneurium (intraneural vascular system). Adapted from Mizisin and Weerasuriya (2011).
Figure 4
Figure 4
Electron microscopy images of rat sciatic nerve after glycerol injection. Analyses of sciatic nerve at 2, 7, 14, 21 and 60 days after injury (D2, D7, D14, D21 and D60), were carried out using electron microscopic images of ultrathin transverse sciatic nerve sections. Briefly, nerve samples were collected and fixed in 2.5% glutaraldehyde and post-fixed in 1% osmium tetroxide solution. Samples were then embedded in epoxy resin (Euromedex, Souffelweyersheim, France). Ultrathin sections (60–100 nm thickness) were collected on 200 mesh copper grids and stained with uranyl acetate and lead citrate. Sections were then examined using a JEM-1011 transmission electron microscope at 80 keV (JEOL, Croissy-sur-Seine, France). Two days after glycerol injection, degenerating myelinated fibers are observed and pre-existing blood vessels are ruptured. There are red blood cells and platelets outside the vessels (D2 right image). However, neo-capillaries are already observed indicating the onset of neo-angiogenesis (D2 left image). One and two weeks after injury, observations show the presence of macrophages. One, two and three weeks after injury, observations show a proliferation in the basal membrane of pre-existing vessels and new vessel growth. In addition, we can note the presence of arterioles surrounded by several neo-capillaries, the presence of macrophages and axonal regrowth (D14 and D21). One month after injury, blood vessels with normal and myelinated axons are observed (D60). The white star shows degenerating myelinated fibers (ovoids). The white and black triangles show blood vessels and neo-vessels respectively. Double black arrows show proliferation of the basal membrane; R: red blood cells; REx: external red blood cells; P: platelets; Per: pericyte; L: blood vessel lumen; M: macrophages; E: endothelial cells; MA: myelinated axons; Ar: axonal regrowth. Scale bars: 1 μm.
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