After Nerve Injury, Lineage Tracing Shows That Myelin and Remak Schwann Cells Elongate Extensively and Branch to Form Repair Schwann Cells, Which Shorten Radically on Remyelination

Abstract

There is consensus that, distal to peripheral nerve injury, myelin and Remak cells reorganize to form cellular columns, Bungner's bands, which are indispensable for regeneration. However, knowledge of the structure of these regeneration tracks has not advanced for decades and the structure of the cells that form them, denervated or repair Schwann cells, remains obscure. Furthermore, the origin of these cells from myelin and Remak cells and their ability to give rise to myelin cells after regeneration has not been demonstrated directly, although these conversions are believed to be central to nerve repair. Using genetic lineage-tracing and scanning-block face electron microscopy, we show that injury of sciatic nerves from mice of either sex triggers extensive and unexpected Schwann cell elongation and branching to form long, parallel processes. Repair cells are 2- to 3-fold longer than myelin and Remak cells and 7- to 10-fold longer than immature Schwann cells. Remarkably, when repair cells transit back to myelinating cells, they shorten ∼7-fold to generate the typically short internodes of regenerated nerves. The present experiments define novel morphological transitions in injured nerves and show that repair Schwann cells have a cell-type-specific structure that differentiates them from other cells in the Schwann cell lineage. They also provide the first direct evidence using genetic lineage tracing for two basic assumptions in Schwann cell biology: that myelin and Remak cells generate the elongated cells that build Bungner bands in injured nerves and that such cells can transform to myelin cells after regeneration.SIGNIFICANCE STATEMENT After injury to peripheral nerves, the myelin and Remak Schwann cells distal to the injury site reorganize and modify their properties to form cells that support the survival of injured neurons, promote axon growth, remove myelin-associated growth inhibitors, and guide regenerating axons to their targets. We show that the generation of these repair-supportive Schwann cells involves an extensive cellular elongation and branching, often to form long, parallel processes. This generates a distinctive repair cell morphology that is favorable for the formation of the regeneration tracks that are essential for nerve repair. Remyelination, conversely, involves a striking cell shortening to form the typical short myelin cells of regenerated nerves. We also provide evidence for direct lineage relationships between: (1) repair cells and myelin and Remak cells of uninjured nerves and (2) remyelinating cells in regenerated nerves.

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

“…As detailed in the following section, Schwann cells provide a further example of adaptive cellular reprogramming. In this case also, cells with a repair‐supportive phenotype, which are normally absent, are generated directly from resident differentiated cells of the injured tissue (Gomez‐Sanchez et al, ) and function to restore tissue homeostasis.…”

“…(c) Structural reorganization, generating extremely elongated, cells, which are about threefold longer than myelin and Remak cells. Lineage tracing has shown that these cells are generated directly from myelin and Remak cells, and that they can convert directly to myelin cells following regeneration (Gomez‐Sanchez et al, ). These cells often carry long, parallel processes, which together with their length, allows repair cells to partly overlap and promotes the formation of the compact cellular columns (Bungner bands—Figures and ), which are obligatory regeneration tracks for regenerating axons (Gomez‐Sanchez et al, ).…”

“…Denervated adult Schwann cells have also been shown to express de novo molecular markers that are low/absent during development, including Sonic Hedgehog (Shh), and Olig1 (Lu et al, ; Bosse et al, ; Arthur‐Farraj et al, ; Fontana et al, ; Lin, Oksuz, Edward Hurley, Wrabetz, & Awatramani, ; reviewed in Jessen & Mirsky, ). Again in contrast to developing cells, denervated cells express high levels of cytokines, recruit macrophages, and activate myelin autophagy to clear myelin (Gomez‐Sanchez et al, ; reviewed in Martini, Fischer, López‐Vales, & David, ; Rotshenker, ; Stratton & Shah, ), Denervated adult cells also adopt a striking elongated and often branched morphology, which is very different from that of Schwann cells in developing nerves, and which enables them to form regeneration tracks, which guide regrowing axons (Gomez‐Sanchez et al, ).…”

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…Repair Schwann cells activate autophagy and phagocytosis mechanisms to remove myelin debris, which inhibit axon regrowth and branching (Brosius Lutz et al 2017; Gomez-Sanchez et al 2015; Mukhopadhyay et al 1994; Shen et al 1998), and promote recruitment of macrophages that further facilitate myelin removal and regeneration (Cattin et al 2015; Fischer et al 2008; Niemi et al 2013). Elongated Schwann cells distal to the injury site form Bands of Bungner, which serve as tracks for axonal regeneration (Arthur-Farraj et al 2012; Gomez-Sanchez et al 2017). …”

Motor and sensory Schwann cell phenotype commitment is diminished by extracorporeal shockwave treatment in vitro

“…The regeneration of axons as well as motor and sensory target innervation after injury is dependent on the capacity of Schwann cells to switch into and maintain a repair phenotype (Büngner cell) . These repair Schwann cells support axonal growth and path‐finding.…”