Schwann Cell Role in Selectivity of Nerve Regeneration

Abstract

Peripheral nerve injuries result in the loss of the motor, sensory and autonomic functions of the denervated segments of the body. Neurons can regenerate after peripheral axotomy, but inaccuracy in reinnervation causes a permanent loss of function that impairs complete recovery. Thus, understanding how regenerating axons respond to their environment and direct their growth is essential to improve the functional outcome of patients with nerve lesions. Schwann cells (SCs) play a crucial role in the regeneration process, but little is known about their contribution to specific reinnervation. Here, we review the mechanisms by which SCs can differentially influence the regeneration of motor and sensory axons. Mature SCs express modality-specific phenotypes that have been associated with the promotion of selective regeneration. These include molecular markers, such as L2/HNK-1 carbohydrate, which is differentially expressed in motor and sensory SCs, or the neurotrophic profile after denervation, which differs remarkably between SC modalities. Other important factors include several molecules implicated in axon-SC interaction. This cell–cell communication through adhesion (e.g., polysialic acid) and inhibitory molecules (e.g., MAG) contributes to guiding growing axons to their targets. As many of these factors can be modulated, further research will allow the design of new strategies to improve functional recovery after peripheral nerve injuries.

A Subpopulation of Schwann Cell-Like Cells With Nerve Regeneration Signatures Is Identified Through Single-Cell RNA Sequencing

“…The ability of peripheral nerves to regenerate autonomously after an injury is mainly contingent on the actions of inherent supporting cells such as Schwann cells ( Jessen et al, 2015 ; Bolívar et al, 2020 ; Nocera and Jacob, 2020 ). As the primary glia and myelin-forming cells within the peripheral nervous system, Schwann cells play an important role in nerve regeneration ( Jessen et al, 2015 ; Bolívar et al, 2020 ; Nocera and Jacob, 2020 ), initiating a reprogramming process after PNI in which they demyelinate and transdifferentiate into repair Schwann cells ( Nocera and Jacob, 2020 ). Several transcription factors and pathways support Schwann cell proliferation, migration, and survival during this process ( Monje, 2020 ; Nocera and Jacob, 2020 ).…”

Peripheral Nerve Regeneration and Muscle Reinnervation

“…The SCs that myelinate intact sensory nerves or encase the non-myelinated small sensory fibers, begin to express sensory-specific neurotrophic factors within 5 days of denervation; the SCs that normally myelinate motor nerve fibers, begin to express their motor specific neurotrophic factors ( Figure 4 A,B) [ 95 , 96 , 97 ]. The mRNA levels of these factors have not reached their peak levels in the motor SCs approximately (~) 10 days after nerve repair when ~50% of the femoral motoneurons regenerate their axons across the suture site ( Figure 2 C and Figure 4 B) [ 29 ].…”

Biomaterials for Neural Tissue Engineering

“…Glial cells give the CNS structural support and protection for neuron networks and guide the developing migrating neurons from their sites of origin to their correct destination and the outgrowth of their axons. They also produce trophic and growth factors to the nervous system regeneration and plasticity and myelin sheaths to insulate the axon and increase the velocity of action potential propagation (oligodendrocytes in CNS and SC in PNS) (Jäkel and Dimou, 2017;Kastriti and Adameyko, 2017;Avraham et al, 2020;Bolívar et al, 2020). Microglia remove debris produced following injury or neuronal death and monitors the CNS, and astrocytes act as bridges that transport nutrients from the capillaries to the neurons and also proliferate to develop astrocytic scars to repair nervous tissue following an injury (reactive gliosis) (Mai and Paxinos, 2012;Butt and Verkhratsky, 2018).…”