Beyond Wrapping: Canonical and Noncanonical Functions of Schwann Cells

Abstract

Schwann cells in the peripheral nervous system (PNS) are essential for the support and myelination of axons, ensuring fast and accurate communication between the central nervous system and the periphery. Schwann cells and related glia accompany innervating axons in virtually all tissues in the body, where they exhibit remarkable plasticity and the ability to modulate pathology in extraordinary, and sometimes surprising, ways. Here, we provide a brief overview of the various glial cell types in the PNS and describe the cornerstone cellular and molecular processes that enable Schwann cells to perform their canonical functions. We then dive into discussing exciting noncanonical functions of Schwann cells and related PNS glia, which include their role in organizing the PNS, in regulating synaptic activity and pain, in modulating immunity, in providing a pool of stem cells for different organs, and, finally, in influencing cancer.

Keywords: Schwann cells; boundary cap cells; satellite cells; terminal Schwann cells.

Figure 1

Schwann cells and Schwann cell precursors are endowed with significant plasticity. (a) Schwann cell precursors derive from the neural crest and maintain some of the neural crest’s multipotency. They can act as multipotent progenitors for several glia and nonglial cell types such as odontoblasts, melanocytes, autonomic neurons, chondrocytes, endoneurial fibroblasts, chromaffin cells, and enteric glia. Enteric glia are shown in detail in panel b. Schwann cell precursors’ main function is to develop into immature and then myelinating or nonmyelinating Schwann cells, which fulfill the canonical functions of axonal ensheathment and myelination. In a process known as axonal sorting, large axons that are destined to be myelinated, such as motor axons or sensory axons that transmit positional information, are segregated by immature Schwann cells from axon bundles into a 1:1 Schwann cell relationship (promyelinating Schwann cells) and finally wrapped by multiple layers of membrane to form the myelin sheath. Nonmyelinating Schwann cells form Remak bundles by ensheathing the small-caliber axons (e.g., sensory axons that transmit pain and temperature information) that remain after the large axons have been sorted out.

Figure 2

Schwann cell functions in physiological and pathological conditions. In addition to canonical functions such as wrapping and myelinating axons and instructing the formation of the node of Ranvier, Schwann cells exert other functions that are required for the physiological function of several organs. For example, a subset of Schwann cells called boundary cap cells actively contribute to the formation of the boundary between the central and peripheral nervous systems (CNS and PNS). Another subset called satellite glia surround neuronal cell bodies in ganglia, such as dorsal root sensory ganglia, where they modulate neuronal activity. Terminal Schwann cells surround the pre- and postsynaptic portion of the neuromuscular junction and actively regulate the activity of this synapse. Other noncanonical Schwann cell functions include the modulation of the innate and adaptive immune response, and the formation and regulation of tactile receptors in the epidermis. Due to their remarkable plasticity, fully differentiated myelinating, nonmyelinating (Remak), and terminal Schwann cells are able to transdifferentiate after injury into repair Schwann cells, which actively contribute to the process of nerve regeneration by clearing myelin and cellular debris and creating basal lamina tracks used by axons to regrow. In pathological conditions, the plasticity, immunomodulatory, and neuromodulatory activities of Schwann cells contribute to neuropathic pain and to the invasion and spreading of cancer cells, the latter likely by dedifferentiating to a phenotype resembling that of repair Schwann cells. Figure adapted with permission from Reed et al. (2021).