Novel approaches for the development of peripheral nerve regenerative therapies.

Abstract

Schwann cells are the myelinating glial cells of the peripheral nervous system (PNS). By establishing lipid-rich myelin sheaths around large-caliber axons, they ensure that electrical signal transmission is accelerated–a process referred to as saltatory signal propagation. Apart from this prominent physiological function, these cells also exert important pathophysiological roles in PNS injuries or diseases. In contrast to the central nervous system (CNS), the adult PNS retains a remarkably high degree of intrinsic regeneration. As a consequence, transected axons and damaged myelin sheaths can be repaired and nerve functionality can be restored. This spontaneous regenerative capacity depends on (inter) actions of macrophages, neurons, and Schwann cells. Although highly specialized and tightly interacting with axons, Schwann cells can revert upon nerve injury or disease to an immature and repair-mediating phenotype (Arthur-Farraj et al., 2012). Dedifferentiated Schwann cells participate in myelin clearance and attract macrophages for further clearance, enabling Wallerian degeneration of distal nerve stumps to proceed. They were also shown to positively influence injured axons and to stimulate regrowth of their tips toward their target cells in the periphery. Finally, re-established axons can be wrapped up again by redifferentiating Schwann cells, thereby generating new isolating myelin sheaths. Thus, spontaneous peripheral nerve regeneration can be mainly attributed to Schwann cells and their particular and specific responses to trauma and disease. This is remarkable cell behavior and implies that these cells have a large capacity to switch and adjust their transcriptional programs, most likely by means of epigenetic controls (Jacob et al., 2011; Heinen et al., 2012). Moreover, multiple interactions with cells and components of the immune system were recently revealed (Tzekova et al., 2014).