Axonal Regeneration: PNS vs CNS

By Marina Artemiou

The term neuroregeneration refers to the regrowth or repair of nervous tissues by the generation of new neurons, glial cells, axons, myelin, or synapses. In nerve injuries that lead to axonal disruption or nerve transection, the nerve becomes divided into a proximal segment which is still attached to cell body, and a distal segment which is disconnected from the neuronal cell body. To achieve full functional recovery, the nerve must successfully undergo three main processes: Wallerian degeneration, which is the clearing process of the distal stump, axonal regeneration of the proximal segment, and end-organ reinnervation (Menorca et al, 2013).

For axonal regeneration to occur, certain criteria must be fulfilled by the damaged nerve. These criteria include the gap between the cut ends of the nerve not exceeding 3 millimetres, neurolemma also known as Schwann sheath must be present, the nucleus of the damaged nerve and endoneurial tube must both be intact, and the point of detachment should not be too close to the cell body. If all prerequisites are fulfilled, the damaged axons will readily regenerate in a multistep process (Menorca et al, 2013).

To understand the process of regeneration as well as the differences in axonal regeneration between the central and peripheral nervous systems, the molecular changes that occur in both the proximal and distal segment as well as the criteria for regeneration must first be explored.

In the proximal segment, and depending on the severity of injury, a limited degree of retrograde axon breakdown occurs, extending proximally from the site of injury up to the level of the first adjacent node of Ranvier. Axonal injury also results in increased permeability to calcium ions (Nagappan et al, 2020). This prolonged influx activates multiple calcium-dependant pathways, most importantly those involved in sealing the transected membrane and growth cone formation. At the same time, a long-range retrograde signal is transported from the site of injury backwards to the cell body, causing a process called chromatolysis to be initiated. This involves the breakup and dispersion of the rough endoplasmic reticulum, the eccentric displacement of the cell nucleus, and increased nuclear expression of transcription factors that alter the pattern of gene expression from axon maintenance to axon regeneration and growth. This is done by upregulating the synthesis of regeneration-associated proteins (RAGs), proteins responsible for neurone survival as well as neurite outgrowth (Nagappan et al, 2020).

In the distal segment, a different set of reactions occurs. Specifically, this segment rapidly degenerates in an active process termed Wallerian degeneration. This is triggered by the depletion of rapidly degrading neuroprotective proteins and enzymes, such as NMNAT2, which are key to maintaining neuronal integrity. Consequently, the myelin sheath and axon membrane begin to disintegrate while cytoskeletal components of the axon are disassembled. In the meantime, Schwann cells detach from the axon, extruding from their myelin sheaths and begin to phagocytose myelin debris and fragmented membrane, however, macrophages eventually infiltrate the area as a response to the cytokines and chemokines secreted by the intact endoneurium. Their actions completely clear the area distally to the injury from growth-suppressive debris, forming a ‘blank slate’ into which the axon of the proximal segment can regenerate. Once all the debris from the distal axons have been cleared, a growth permissive environment is formed, and regeneration begins (Deumens et al, 2010).

At the distal tip of the proximal segment the axon begins to form a growth cone. This is a dynamic structure, which bears receptor-rich lamellipodia and filopodia that guide the regenerating axon towards its final target. At the same time, Schwann cells down-regulate their expression of myelin genes, dedifferentiate, and rapidly proliferate growing in ordered columns along the endoneurial tube, creating Bands of Büngner, which offer structural guidance to the regenerating axon. The direction of movement of the growth cone is also heavily dependent on the presence of particular receptors in its membrane as well as guidance ques expressed or secreted by the endoneurial tube, Schwann cells and the target organ (Deumens et al, 2010).

All the processes mentioned above, that collectively lead to axonal regeneration, only occur in neurones of the peripheral nervous system. In contrast, neurones in the central nervous system do not readily regenerate and functional recovery following central nervous system nerve damage is not usually possible. It is limited by the inhibitory influences of glial cells and extracellular environment. The hostile, non-permissive growth environment is, in part, created by the migration of myelin-associated inhibitors, astrocytes, oligodendrocytes, oligodendrocyte precursors, and microglia, in addition to the slower debris clearance which also impedes axonal re-growth. Consequently, axonal regeneration in the CNS does not usually occur leaving patients with CNS damage unable to completely recover (Huebner et al, 2009).

While it is now widely accepted that transected nerves within the CNS cannot regenerate their axons, the conditions which are responsible for creating this non-permissive environment have been identified and recent advances in our understanding of factors which limit CNS regeneration and those which facilitate PNS regeneration have led to research into therapies which allow some degree of recovery for neurones of the CNS (Huebner et al, 2009).

References:

1. Menorca, R.M.G., Fussell, T.S. & Elfar, J.C. (2013) Peripheral Nerve Trauma: Mechanisms of Injury and Recovery. Hand clinics. [Online] 29 (3), 317–330. Available from: doi:10.1016/j.hcl.2013.04.002.
2. Nagappan, P.G., Chen, H. & Wang, D.-Y. (2020) Neuroregeneration and plasticity: a review of the physiological mechanisms for achieving functional recovery postinjury. Military Medical Research. [Online] 7 (1), 30. Available from: doi:10.1186/s40779-020-00259-3.
3. Deumens, R., Bozkurt, A., Meek, M.F., Marcus, M.A.E., et al. (2010) Repairing injured peripheral nerves: Bridging the gap. Progress in Neurobiology. [Online] 92 (3), 245–276. Available from: doi:10.1016/j.pneurobio.2010.10.002.
4. Huebner, E.A. & Strittmatter, S.M. (2009) Axon Regeneration in the Peripheral and Central Nervous Systems. Results and problems in cell differentiation. [Online] 48, 339–351. Available from: doi:10.1007/400_2009_19.