The regulation of the homeostasis and regeneration of peripheral nerve is distinct from the CNS and independent of a stem cell population

Abstract

Peripheral nerves are highly regenerative, in contrast to the poor regenerative capabilities of the central nervous system (CNS). Here, we show that adult peripheral nerve is a more quiescent tissue than the CNS, yet all cell types within a peripheral nerve proliferate efficiently following injury. Moreover, whereas oligodendrocytes are produced throughout life from a precursor pool, we find that the corresponding cell of the peripheral nervous system, the myelinating Schwann cell (mSC), does not turn over in the adult. However, following injury, all mSCs can dedifferentiate to the proliferating progenitor-like Schwann cells (SCs) that orchestrate the regenerative response. Lineage analysis shows that these newly migratory, progenitor-like cells redifferentiate to form new tissue at the injury site and maintain their lineage, but can switch to become a non-myelinating SC. In contrast, increased plasticity is observed during tumourigenesis. These findings show that peripheral nerves have a distinct mechanism for maintaining homeostasis and can regenerate without the need for an additional stem cell population.

Schwann cell plasticity‐roles in tissue homeostasis, regeneration, and disease

“…Larger peripheral nerves contain several fascicles that are surrounded by a common epineurium (Jessen et al, ; Zochodne, ). The majority of the cells in the peripheral nerve endoneurium are SCs with a 2:1 ratio of mSCs to nmSCs (Salonen, Aho, Roytta, & Peltonen, ; Stierli et al, ). In addition to SCs, the endoneurium also contains tissue‐resident macrophages, endothelial cells and associated pericytes (Jessen et al, ).…”

“…In addition to SCs, the endoneurium also contains tissue‐resident macrophages, endothelial cells and associated pericytes (Jessen et al, ). Furthermore, a new cell type was characterised recently that, while previously described as endoneurial fibroblasts (Joseph et al, ), is of unknown function in the homeostatic nerve, expresses markers of both pericytes and mesenchymal cells and makes contacts with different cell types within the endoneurium leading to them being re‐named as tactocytes (Carr et al, ; Stierli et al, ).…”

“…Peripheral nerve is a highly quiescent tissue in the adult. Using cumulative long‐term 5′ ethynyl‐2′‐deoxyurdine (EdU) labeling, together with immunostaining of endogenous cell‐type specific markers, it was shown that that proliferation rates of all cell types within the mouse endoneurium is extremely low (Stierli et al, ). Most notably, the main cell type of the nerve, the mSC, appears not to divide at all, indicating that once this cell has matured it exists for the lifespan of the animal.…”

“…mSCs are the most abundant cells within the peripheral nerve trunk (Stierli et al, ). By forming a compact myelin sheath around large caliber axons (>1 μm), they provide electrical insulation which allows rapid, saltatory conduction of action potentials over the long distances covered by the PNS (Salzer, ).…”

Signatures of altered DNA methylation gene expression after central and peripheral nerve injury

“…A sequential response triggered after peripheral nerve injury (PNI) is known as Wallerian degeneration (Jang et al, ). Subsequently, Schwann cells remove axonal and myelin debris, and secrete cytokines, thereby accelerating axonal regeneration (Ma, Duong, Moran, Junaidi, & Svaren, ; Stierli et al, ). In addition, the peripheral nerve microenvironment contains a variety of neurotrophic factors or growth factors, which play an irreplaceable role in nerve regeneration.…”