Schwann cells regulate sensory neuron gene expression before and after peripheral nerve injury

Abstract

Sensory neurons in the PNS demonstrate substantial capacity for regeneration following injury. Recent studies have identified changes in the transcriptome of sensory neurons, which are instrumental for axon regeneration. The role of Schwann cells (SCs) in mediating these changes remains undefined. We tested the hypothesis that SCs regulate expression of genes in sensory neurons before and after PNS injury by comparing mice in which LDL Receptor-related Protein-1 (LRP1) is deleted in SCs (scLRP1 mice) with wild-type (scLRP1 ) littermates. LRP1 is an endocytic and cell-signaling receptor that is necessary for normal SC function and the SC response to nerve injury. scLRP1 mice represent a characterized model in which the SC response to nerve injury is abnormal. Adult DRG neurons, isolated from scLRP1 mice, with or without a conditioning nerve lesion, demonstrated increased neurite outgrowth when cultured ex vivo, compared with neurons from wild-type mice. Following sciatic nerve crush injury, nerve regeneration was accelerated in vivo in scLRP1 mice. These results were explained by transcriptional activation of RAGs in DRG neurons in scLRP1 mice prior to nerve injury. Although the presence of abnormal SCs in scLRP1 mice primed DRG neurons for repair, nerve regeneration in scLRP1 mice resulted in abnormalities in ultrastructure, principally in Remak bundles, and with the onset of neuropathic pain. These results demonstrate the importance of SCs in controlling RAG expression by neurons and the potential for this process to cause chronic pain when abnormal. The SC may represent an important target for preventing pain following PNS injury.

Satellite glial cells in sensory ganglia express functional transient receptor potential ankyrin 1 that is sensitized in neuropathic and inflammatory pain

“…[4][5][6] This structure permits bidirectional communication and functional interactions between sensory neurons and SGCs, including activation of neighboring neurons and SGCs. 7,8 There is now growing evidence that normal neuronal activity in DRG depends on neuron-glia interactions and that abnormal SGC function may contribute to painful conditions. [9][10][11][12][13] Thus, there is a need to more fully understand the nature of SGC interactions with primary sensory neurons and their role in chronic pain.…”

Emerging neurotechnology for antinoceptive mechanisms and therapeutics discovery

“…Along these lines, it may be worthwhile to investigate phenotypic contributions of either primary or hiPSC-derived non-neuronal cell types (satellite glia, Schwann cells) in heterogeneous culture models, as it has been demonstrated in other hiPSC neuron models that the presence of support cells (glia, oligodendrocytes) facilitates synaptogenesis, phenotypically relevant mRNA expression, and functional maturation (Ishii et al, 2017;Kayama et al, 2018;Odawara et al, 2014;Schutte et al, 2018;Tang et al, 2013). In the case of chronic pain development, satellite glia and Schwann cells have been shown to facilitate sensitization and intercellular signaling via gap junctions and transmitter release (e.g., ATP) (Campana, 2007;De Logu et al, 2017;Hartlehnert et al, 2017;Huang et al, 2013;Kodama et al, 2017;Poplawski et al, 2018;Takeda et al, 2009). Therefore, developing combinatorial imaging-electrophysiological approaches may add highly relevant content without diminishing density or throughput.…”

The Mechanisms of Peripheral Nerve Preconditioning Injury on Promoting Axonal Regeneration

“…The LDL receptor-related protein-1 (LRP1) is the cell-signaling receptor required for normal SC function. Comparing scLRP1-/- mice with wild-type littermates with and without peripheral nerve injury, Poplawski et al provide evidence that SCs regulate the RAG expression in DRGs [ 76 ]. In addition, other cell type endothelial cells are also involved in nerve regrowth.…”