Primary sensory neurons in the dorsal root ganglia transmit sensory information from peripheral tissues to the spinal cord and brain. These neurons have a pseudounipolar morphology with a single axon that divides into two branches within the ganglion: one branch runs along the peripheral nerves, the other centrally along the dorsal root into the spinal cord. While injuries to the peripheral axon usually lead to successful axon regeneration, the growth of the centrally projecting axon remains weak and does not lead to functional recovery.
Numerous studies have exploited the differential response of the two axon branches to dissect the processes that govern the regeneration programme of axons. It has been found that successful axonal regeneration into the periphery is associated with specific transcriptional and epigenetic changes. However, the regulation of sensory neuron regeneration is not entirely cell autonomous.
Axotomised peripheral neurons benefit from a supportive environment, because nerve injuries also induce changes in gene expression in satellite glial cells surrounding the cell body and in Schwann cells that wrap around the axon. In addition, macrophages, which develop after an injury mainly from circulating precursor cells of the bone marrow, contribute to axon regeneration by clearing cell debris, positively influencing vascularisation in the injury area and regulating the function of Schwann cells. However, they also contribute to neuropathic pain after nerve injuries.
In contrast to macrophages in the peripheral nervous system, only a small proportion of macrophages in ganglia originate from circulating precursors in the bone marrow after an injury, because macrophages can self-renew through local proliferation. In a paper published in PNAS last year, the research group led by Valeria Cavalli from St. Louis (USA) examined the origin of ganglion macrophages after nerve injuries.
Using a model of depletion (using PLX73086, a selective inhibitor of the colony-stimulating factor 1 receptor) and repopulation of these cells, a total of four groups of macrophages could be distinguished. The largest proportion originates from the local proliferation of residual macrophages, which contribute to the promotion of axon regeneration in vivo and to the so-called preconditioning effect. Other smaller populations include microglia-like cells and macrophage-like satellite cells. Single-cell transcriptome data and cell communication analyses showed that macrophages express the neuro- and glia-protective ligand prosaposin and communicate with satellite cells via the prosaposin receptor GPR37L1.
The specific functions of the various macrophage subtypes need to be investigated in more detail in future studies in order to develop therapeutic approaches that can be used to treat nerve injuries and enable regeneration without pain.
Reference:
Feng R, Muraleedharan Saraswathy V, Mokalled MH, Cavalli V (2023) Self-renewing macrophages in dorsal root ganglia contribute to promote nerve regeneration. Proceedings of the National Academy of Sciences 120:e2215906120
Image credit: iStock/Artur Plawgo
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