Guest article by cand. med. Christopher Egger (Medical University of Innsbruck)
It has been known for many years that Schwann cells in the peripheral nerves play a central role in axon regeneration. After an acute lesion, they secrete numerous molecules that support or enable the outgrowth of injured nerve fibers.
However, the release of neurotrophic factors and extracellular matrix proteins is quickly depleted in older patients and cannot be maintained in nerves that have been severed for a long time (a condition known as chronic denervation). As part of the ageing process, some of the Schwann cells enter senescence, i.e. the glia can no longer divide and can only fulfill their metabolic tasks to a limited extent.
In a paper recently published in the prestigious EMBO journal, Andrés Fuentes-Flores and colleagues deal with this problem and show in cell culture (in vitro), but also in animal experiments in vivo, that senescent Schwann cells secrete numerous proteins that directly attack the growth cone of a regenerating axon and can thus suppress regeneration. In particular, a reduced expression of c-Jun (a transcription factor essential for the conversion of neuronal metabolism and the reprogramming of glial cells) was detected. Furthermore, cytokine array analyses identified several candidates that may be responsible for the inhibition of regeneration.
In aging mice and in chronic denervation, elimination of senescent Schwann cells by systemic treatment with senolytic drugs or by genetic targeting improved nerve regeneration and functional recovery. Furthermore, the expression of c-JUN was normalized and the signs of inflammation in the lesioned nerve decreased. Of 111 proinflammatory cytokines analyzed, 25 were downregulated after senolytic treatment. Three of them showed a significant reduction under both conditions: IL-6, CCL19 and CXCL1. Interestingly, macrophages suppress Schwann cell proliferation and maturation through the secretion of IL-6, and CXCL1 is associated with the inhibition of peripheral axonal growth.
Taken together, the present data show that senescent Schwann cells have an inhibitory effect on axonal regeneration and in chronic denervation. Elimination of these cells or neutralization of the factors secreted by them therefore represents a new opportunity for therapeutic intervention to improve axonal regeneration and functional recovery after peripheral nerve injury.
Reference:
Fuentes-Flores A, Geronimo-Olvera C, Girardi K, ..., Campisi J, Court FA (2023) Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury. EMBO Molecular Medicine 15: e17907
Image credits: Fig. 1D from https://doi.org/10.15252/emmm.202317907