Peripheral nerve derived fibroblasts promote neurite outgrowth in adult dorsal root ganglion neurons more effectively than skin-derived fibroblasts

Although fibroblasts (Fb) partially consist of peripheral nerves and are involved in the regenerative process associated with a peripheral nerve injury (PNI), detailed information regarding their characteristics is largely lacking. The objective of the current study was to investigate the capacity of Fb derived from peripheral nerves to stimulate the outgrowth of neurites from adult dorsal root ganglion (DRG) neurons and to clarify their molecular characteristics. Fb were primally prepared from the epineurium (Epn) and parenchyma (Par) of rat sciatic nerves and skin (Skn). The Fb derived from Epn (Fb-Epn) showed the greatest neurite outgrowth effect, followed by the Fb derived from parenchyma (Fb-Par), indicating that Fb derived from nerves promote neurite outgrowth more effectively than Skn-derived Fb (Fb-Skn). Although both secreted and cell-surface factors contributed evenly to the neurite promoting effect of nerve derived Fb, in crush and transection injury models, Fb were not closely associated with regenerating axons, indicating that only factors that are secreted from Fb are available to regenerating axons. A transcriptome analysis revealed that the molecular profiles of these Fb were distinctly different and that the gene expression profiles of secreted factors that promote axonal growth are unique to each Fb. These findings indicate that Fb are molecularly and functionally different depending on their localization in nerve tissue and that Fb-Epn might be involved more than was previously thought in axon regeneration after PNI. Comparative gene expression profiling analysis of RNA-seq data for three types of fibroblasts from epineurium, parenchyma and skin (Fb-Epn, Fb-Par, Fb-Skn)