Schwann Cells: Development and Role in Nerve Repair.

Schwann Cells: Development and Role in Nerve Repair Kristján R. Jessen1, Rhona Mirsky1, and Alison C. Lloyd2 1 Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom 2 MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom Correspondence: Schwann cells develop from the neural crest in a well-defined sequence of events. This involves the formation of the Schwann cell precursor and immature Schwann cells, followed by the generation of the myelin and nonmyelin (Remak) cells of mature nerves. This review describes the signals that control the embryonic phase of this process and the organogenesis of peripheral nerves. We also discuss the phenotypic plasticity retained by mature Schwann cells, and explain why this unusual feature is central to the striking regenerative potential of the peripheral nervous system (PNS). he myelin and nonmyelin (Remak) Schwann cells of adult nerves originate from the neural crest in well-defined developmental steps (Fig. 1). This review focuses on embryonic development (for additional information on myelination, see Salzer 2015). We also discuss how the ability to change between differentiation states, a characteristic attribute of developing cells, is retained by mature Schwann cells, and explain how the ability of Schwann cells to change phenotype in response to injury allows the peripheral nervous system (PNS) to regenerate after damage. T TWO TYPES OF EMBRYONIC NERVES Adult nerves are stable structures in which the nerve fibers are protected structurally by a collagen-rich, vascularized extracellular matrix (the endoneurium) linked to the basal lamina surrounding each axon – Schwann cell unit. The endoneurial environment is further protected by a surrounding multilayered cellular tube (the perineurium) that shields the nerve fibers from unwanted cells and molecules (Fig. 2). A more dynamic and radically different structure, reminiscent of axon – glial organization in the central nervous system (CNS), is seen in early embryonic nerves (embryo day E14/15 in rat hind limb and E12/13 in mouse). These nerves consist of tightly packed axons and flattened, glial cell processes without significant extracellular space, matrix, or basal lamina. The glial cell bodies lie among the axons inside the nerve or at the nerve surface. These cells represent the first stage of the Schwann cell lineage, Schwann cell precursors (Figs. 3 and 4). Editors: Ben A. Barres, Marc R. Freeman, and Beth Stevens Additional Perspectives on Glia available at www.cshperspectives.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a020487 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020487 1 K.R. Jessen et al. Schwann cell precursor lineage Melanocytes Endoneurial fibroblasts Myelin Schwann cell Axon Parasympathetic neurons Repair (Bungner) Schwann cell Promyelin Schwann cell Radial sorting Neural crest Schwann cell precursor E12/13 Nonmyelin (Remak) Schwann cell Immature Schwann cell E15/16 Early postnatal Adult Figure 1. Main transitions in the Schwann cell precursor (SCP) lineage. The diagram shows both developmental and injury-induced transitions. Black uninterrupted arrows, normal development; red arrows, the Schwann cell injury response; stippled arrows, postrepair reformation of myelin and Remak cells. Embryonic dates (E) refer to mouse development. (Modified from Jessen and Mirsky 2012; reprinted, with permission and with contribution from Y. Poitelon and L. Feltri.) Peripheral nerve — transverse section Epineurial connective tissue Myelin Schwann cell Axons Endoneurial connective tissue Macrophage Nonmyelin (Remak) Schwann cell Cellular perineurium Blood vessel Fibroblast Fascicle Figure 2. Diagram showing the architecture and main cellular components of an adult peripheral nerve. The main cellular structures within the nerve and the connective tissue compartments and the perineurium that protects them are indicated. This nerve contains one fascicle; larger nerves consist of several fascicles embedded in a common epineurium. The perineurium shown here, as a single cell layer, is most often multilayered. The drawing does not show the basal lamina that surrounds individual Schwann cell/axon units, blood vessels, and perineurial cells. 2 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020487 Schwann Cell Development and Nerve Repair Neural crest Immature Sch Other features Axon associated No change Molecular markers Sch precursors Upregulation ECM associated Axon associated ErbB3 L1 p75NTR Sox10 ErbB3 L1 p75NTR Sox10 Basal lamina Autocrine survival ErbB3 L1 p75NTR Sox10 BFABP Dhh Po GAP43 PMP22 PLP Connexin 29 PrPC Astrotactin Serpin2 NFIB Cad19 GFAP S100 Oct6 O4 MAL Galectin Desmoyokin Reelin Decorin Downregulation α4 integrin AP2 Ncad Cad19 Figure 3. The phenotype of key stages in embryonic Schwann cell development. Each stage involves characteristic relationships with surrounding tissues and distinctive signaling properties (indicated in the panels immediately below the lineage drawing). Also shown are some of the molecular markers of the lineage. They fall into three groups: (1) markers that show no significant change between the three stages; (2) markers that are up-regulated during development (some of these are up-regulated at the crest to Schwann cell precursor transition; another group is up-regulated at the Schwann cell precursor to immature Schwann cell transition); (3) markers that are down-regulated at the Schwann cell precursor to immature Schwann cell transition. Sch, Schwann cell. (Modified from Jessen and Mirsky 2005; reprinted, with permission. See the original reference for detailed references to the molecules shown.) Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020487 3 K.R. Jessen et al. The period around E16 in rat (E14 mouse) is, therefore, a turning point when generation of Schwann cells from precursors coincides with the establishment of a tissue architecture similar to that of adult nerves. SCP SCHWANN CELL PRECURSORS iSch Developmental Potential ∗ Figure 4. Schwann cell precursors (SCP) and imma- ture Schwann cells (iSch) in embryonic nerves. (Upper panel) Transverse section of E14 rat sciatic nerve. Schwann cell precursors are embedded among the axons (downward large arrow) and at the surface of the nerve (upward large arrow). A dividing Schwann cell precursor is also seen (small arrow). Connective tissue (turquoise) is not found inside the nerve. (Lower panel) Transverse section of E18 rat sciatic nerve. One or a few immature Schwann cells together surround several axons, forming compact groups or families (asterisk). A dividing Schwann cell is seen (double arrows). Connective tissue (turquoise) containing blood vessels (large arrow) is present throughout the nerve surrounding the (...truncated)