Novel neuron-Schwann cell co-culture models to study peripheral nerve degeneration and regeneration.

Schwann cells are glial cells in the peripheral nervous system that provide trophic support for the growth and maintenance of sensory, motor, and autonomic neurons and ensheath their axons in either a myelinating or an unmyelinating form. Myelinating Schwann cells wrap around large-diameter axons to form multilayered myelin structures essential for the rapid action potential propagation from one node of Ranvier to the next node (saltatory conduction). In contrast, non-myelinating Schwann cells surround several small-diameter axons to form Remak bundles. Following peripheral nerve injury, Schwann cells lose axonal contact and change their phenotype in favor of axonal regeneration and functional restoration. These "de-differentiated" Schwann cells migrate into the site distal to the injury and phagocytose axonal and myelin debris together with macrophages (Wallerian degeneration). Subsequently, they proliferate to constitute the bands of Büngner which act as guideposts for regenerating axons and provide various neurotrophic factors and chemokines that help axonal reinnervation toward target tissues and protect injured neurons from degeneration and cell death. At the final regeneration stage, the "re-differentiated" Schwann cells remyelinate growing large diameter axons or ensheath small diameter axons forming Remak bundles (Sango et al., 2017). Schwann cell abnormalities and/or their crosstalk with neurons lead to demyelinating neuropathy (myelinopathy) development and progression. These deviations are also involved in the manifestations of axons (axonopathy) and neuronal cell bodies (neuronopathy) (Niimi et al., 2019).