Abstract
This paper investigates how distinct myelination strategies of neurons in the central nervous system (CNS) and peripheral nervous system (PNS) influence their regenerative capacities following injury. Neurons are important to the human body as they act as a point of relay to receive and transmit nerve signals to and from the central nervous system. They allow for communication between the body and the brain, serving as connection points between neurological structures. Unlike PNS neurons, which benefit from thorough myelin sheath repair and regeneration facilitated by Schwann cells, CNS neurons face limited regenerative potential due to the inhibitory environment created by oligodendrocytes and associated myelin debris. Researchers have employed comparative analyses of myelination patterns and regenerative responses in both systems. Results suggest that the PNS’s supportive microenvironment significantly enhances neuronal recovery, whereas the CNS’s intrinsic and extrinsic inhibitory factors substantially impair regeneration. These findings elucidate the fundamental differences in myelination and regeneration between the CNS and PNS, providing insights into potential therapeutic strategies to improve neuronal repair in the CNS by modifying myelination processes. Neuronal regeneration is a complex process influenced by the myelination strategies of basal ganglia neurons in the central nervous system and the peripheral nervous system. This article explores how these differences in myelination impact the regenerative capacities of neurons following injury, drawing on recent research to elucidate these mechanisms. This research underscores the need for targeted interventions to overcome regenerative barriers in the CNS and enhance recovery outcomes for patients with neurological injuries. Understanding the Influence of Myelination on Neuronal Regeneration: CNS vs. PNS
Myelination, the process of forming a myelin sheath around nerves, is crucial for efficient signal transmission, allowing nerve impulses to travel faster, and prompting quicker responses to stimuli. When damage to myelin occurs, it slows the rate of impulses, leading to impaired neurological function. In the PNS, Schwann cells produce myelin and play an active role in promoting neuronal repair. The central nervous system(CNS) consists of portions of the nervous system within the brain and spinal cord. The Peripheral Nervous system(PNS) consists of cranial nerves and spinal nerves. It is important for connecting the body to the central nervous system. If myelinated, neurons found within the CNS will be done so through oligodendrocytes— glial cells that extend their plasma membrane, known as plasmalemma around multiple axon terminals. However, PNS neurons are not myelinated by oligodendrocytes, but rather Schwann cells. These cells will instead wrap the plasma membrane of their full cell body around one segment of a single neuron’s axon terminal. Multiple Schwann cells are necessary to myelinate one axon terminal whereas one oligodendrocyte can myelinate various neurons simultaneously. These differences ultimately mean that damage to PNS neurons can be repaired more efficiently, as it would require less
energy to replace or repair Schwann cells over oligodendrocytes. This issue is present due to oligodendrocyte myelination in the CNS can be highly problematic to the body as a whole. This is because the CNS is largely responsible for coordinating body processes such as movement, respiration and nutrition. Therefore, irreparable damage to the CNS can, in many instances, prove fatal or cause life-long complications, thus underscoring the need for exploration into possible methods of enhancing CNS regeneration.
Response to injury in the CNS vs the PNS
Upon injury, Schwann cells clear debris— such as fragments of cell organelles and proteins which can act as physical barriers to axonal growth and trigger inflammatory responses— and secrete growth factors, creating a supportive environment that facilitates neuronal regrowth and functional recovery (Jessen & Mirsky, 2005).
Conversely, in the CNS, oligodendrocytes produce myelin, but their role in regeneration is less supportive. Following injury, the CNS environment is characterised by the presence of inhibitory molecules such as Nogo-A, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp), which hinder neuronal regrowth (Liu et al., 2006). These molecules are produced primarily with the purpose of inhibiting axonal regeneration. Although the genes to produce these molecules can be expressed within in PNS neurons, its usage is largely unnecessary in these regions, thus produced less if produced at all. They are mainly used for occurrences of apoptosis but are still produced regardless. Additionally, the clearance of myelin debris is less efficient, exacerbating the inhibitory environment (Miller et al., 2007) In the CNS, debris is cleared by microglia, which will act as phagocytes, engulfing bacteria. However, this process is less efficient because it is inhibited by the larger mass of oligodendrocytes and because the microglia tend to work with less speed, thus allowing for more inflammation to be triggered. Comparative Analysis of Regenerative Capacity
Studies comparing regenerative outcomes between CNS and PNS reveal a stark contrast. In the PNS, regeneration is robust due to the supportive actions of Schwann cells and the relatively permissive environment for axonal growth. For example, upon injury they clear myelin debris, secrete neurotrophic factors (e.g., NGF, BDNF, and GDNF), and form Büngner bands—structures that act as guiding pathways for regenerating axons. This process is complemented by the permissive extracellular matrix and less inhibitory signalling compared to the CNS, allowing axons to grow and reconnect to target tissues. (Chen et al., 2016). Axonal growth is essential for allowing damaged axons to sprout new growth cones, enabling them to extend a new axon to its target point and thus regenerating the neuron. For instance, peripheral nerve injuries often result in significant recovery, with axons effectively regrowing and reinnervating target tissues.
In contrast, the CNS demonstrates limited regenerative capacity. Research using animal models has shown that CNS neurons face substantial barriers to regeneration due to both intrinsic factors (e.g., the limited growth potential of mature CNS neurons) and extrinsic factors (e.g., the inhibitory molecules present in the CNS) (Silver & Miller, 2004). For example, lesions in the spinal cord or brain often result in permanent functional deficits, as axonal regrowth is impeded by these inhibitory cues and the inefficiency in debris clearance (Fitch & Silver, 2008).
Potential Therapeutic Strategies
Damage to CNS neurons can result in a wide range of neurological issues due to the central role these neurons play in transmitting signals throughout the brain and spinal cord. Such damage can lead to motor impairments, including paralysis or loss of coordination, as seen in spinal cord injuries and stroke. Sensory deficits, such as numbness, tingling, or loss of sensation, may occur when sensory pathways are disrupted. Cognitive functions can also be affected, resulting in memory loss, difficulties with attention, or impaired reasoning, as seen in traumatic brain injuries or neurodegenerative diseases like multiple sclerosis. Additionally, damage to CNS neurons may cause chronic pain, spasticity, or autonomic dysfunctions, such as difficulty regulating blood pressure, breathing, or bladder control. Because CNS neurons have limited regenerative capacity, these neurological deficits can be long-lasting or permanent, significantly impacting a person’s quality of life.
Damage to PNS neurons tends to have less enduring effects due to their myelination strategies and how they differ from CNS strategies. Understanding these differences highlights the need for targeted therapeutic strategies to enhance CNS regeneration and informs possible approaches to address this need while helping those with the previously mentioned neurological issues. Research focuses on several approaches, including modulation of inhibitory signals, promoting oligodendrocyte precursor cell maturation, and improving myelin debris clearance (Yiu & He, 2006). These therapies allow CNS neurons to imitate the strengths of PNS regeneration by enabling the creation of a more supportive environment for growth. Additionally, biomaterials and gene therapies are being explored to create a more favourable environment for CNS repair (Benowitz & Carmichael, 2010). Biomaterials such as hydrogels provide a physical scaffold that supports cell adhesion, axonal growth, and the localised delivery of neurotrophic factors. For instance, polyethylene glycol (PEG)-based hydrogels can bridge spinal cord injuries by filling lesion cavities and creating a supportive matrix for regenerating axons to grow and reconnect to their targets (Chen et al., 2016). Similarly, nanofiber scaffolds mimic the extracellular matrix, providing a guidance pathway for axonal regeneration and promoting Schwann cell migration, which are essential for rebuilding damaged neural connections (Wang et al., 2016). Biodegradable polymers such as polylactic acid (PLA) and polycaprolactone (PCL) serve as temporary conduits or scaffolds that provide structural support during the critical early phases of repair. These materials gradually degrade as new tissue forms, eliminating the need for surgical removal (Liu et al., 2016). In addition to biomaterials, gene therapies play a significant role in enhancing CNS repair. One approach involves delivering neurotrophic factors like BDNF (Brain-Derived Neurotrophic Factor) or NT-3 (Neurotrophin-3), which support neuron survival, stimulate axonal regeneration, and enhance functional recovery by creating a pro-growth environment (Chen et al., 2016). Another strategy focuses on modulating inhibitory molecules such as Nogo-A and chondroitin sulfate proteoglycans (CSPGs), which are known to inhibit axonal growth. Gene therapies targeting these molecules can reduce their expression, thereby removing molecular barriers and allowing axons to regenerate (Wang et al., 2016). Additionally, gene therapies involving stem cell modifications enable the expression of growth-promoting factors like VEGF (Vascular Endothelial Growth Factor), enhancing the survival and repair potential of transplanted stem cells (Liu et al., 2016).
Together, these advancements in biomaterials and gene therapies provide structural support, facilitate axonal regeneration, and overcome molecular barriers, creating a more permissive environment for CNS repair. Conclusion
The different myelination strategies between the CNS and PNS play a crucial role in determining their respective regenerative capacities. While the PNS benefits from a supportive regenerative environment created by Schwann cells, the CNS is hampered by inhibitory factors and inefficient debris clearance. Addressing these challenges through targeted therapies could improve outcomes for individuals with neurological injuries and advance our understanding of neuronal regeneration.
Written by: Natessa Heastie
Works Cited
Benowitz, L. I., & Carmichael, S. T. (2010). Promoting axonal growth to enhance recovery from neurological injury. Journal of Neurotrauma, 27(5), 581-594.
Chen, K. K., Wang, Y., & Liu, Q. (2016). Peripheral nerve injury and regeneration: A comprehensive review. Journal of Neuroscience Research, 94(11), 1243-1251.
Fitch, M. T., & Silver, J. (2008). CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regenerating axons. Neuron, 56*(2), 225-234.
Jessen, K. R., & Mirsky, R. (2005). The repair Schwann cell and its function in regenerating nerves. Journal of Physiology, 566(1), 33-40.
Liu, Y., Wang, Y., & Hu, B. (2006). The role of myelin-associated inhibitors in CNS axon regeneration. Neurobiology of Disease, 21(1), 27-37.
Miller, R. H., & Thomas, A. C. (2007). Myelin and oligodendrocytes in the central nervous system. Journal of Neuroscience Research, 85(12), 2922-2935.
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