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  • Following nerve injury Shh expression is upregulated in


    Following nerve injury, Shh expression is upregulated in neuronal cell bodies of the facial and sciatic nerves. Additionally, Shh appears to be required for normal regeneration in vivo, and promotes motor neuron survival in vitro (Martinez et al., 2015; Akazawa and Kohsaka, 2007). Based on these observations, we postulated that the Hedgehog pathway may play a role in the reformation of the connective tissue components of the facial nerve after transection injury.
    Discussion To date, Shh expression has been shown to increase within the neuronal soma in response to sciatic and facial nerve injury, and to be required for both neuronal survival and neuronal outgrowth (Martinez et al., 2015; Akazawa and Kohsaka, 2007). However, the cellular and molecular targets of Hh ligand within the regenerating nerve are still largely unknown. Our results indicate that Hh-responsive fibroblasts exist in the uninjured facial nerve, proliferate in response to injury, and appear to play a role in restoring the nerve's three-dimensional architecture following nerve transection. Endoneurial and perineurial fibroblasts are a heterogeneous cell population that typically express NG2 and Fibronectin, among other markers, and are found scattered between nerve fibers in the endoneurium, adjacent to the vasa nervorum, and within the perineurium (Parrinello et al., 2010; Richard et al., 2012, Richard et al., 2014). In development, they contribute to the formation of the epineurium, perineurium, and endoneurium, forming a connective tissue sheath that provides insulation and support to Schwann NPE-caged-proton synthesis and axons. This process is dependent upon Desert Hedgehog activity (Parmantier et al., 1999). Although this study indicates that Hedgehog-activated fibroblasts may play an important role in facial nerve regeneration, the details of this role of Hh requires additional characterization through pharmacologic and genetic modulation of the Hh pathway during nerve regeneration. In multiple other organ systems, Hedgehog signaling activates an early fibrotic response in tissue mesenchyme that is intimately involved in tissue regeneration (Roberts et al., 2017). The function of the Gli1+ cells in the facial nerve may be similar. These cells appear to maintain an intimate connection with regenerating axons, enveloping them and their respective SCs, likely contributing to a regenerated scaffold where the nerve sheath has been disrupted by injury. They express the chondroitin sulfate NG2, which has been shown to be upregulated at the site of a nerve axotomy, and which is thought to play a role in guiding regenerating axons to the distal nerve stump (Rezajooi et al., 2004). These cells also appear to contribute to Fibronectin secretion within the nerve. Fibronectin is a ubiquitous extracellular matrix (ECM) component, and an integral component of the wound ECM, providing structure and support as tissue rebuilds after injury through its interactions with integrins, collagens, and laminins in the nerve (Singh et al., 2010; Liu et al., 2009). Fibronectin is also thought to be the preferred ECM component for motor neurite outgrowth during development (Gonzalez-Perez et al., 2016), and has been recently highlighted as an important substrate for three-dimensional neurite outgrowth in vitro (Harris et al., 2017). Our findings thus highlight a novel role for Hedgehog signaling in the regenerating nerve, whereby Hh-responsive mesenchymal cells actively participate in the response to injury. Questions that merit additional study include an investigation of the source and subtype of Hedgehog ligand at the injury site. Potential sources include Dhh from Schwann cells responding to injury (Hashimoto et al., 2008), Shh from NPE-caged-proton synthesis the regenerating neurites themselves (Martinez et al., 2015), or a combination thereof. Additionally, it is unknown whether or not the Gli1+ fibroblasts are an absolute requirement for successful nerve regeneration, or for restoration of the cross-sectional anatomy of a regenerating nerve. Future investigations may include both genetic and pharmacologic Gli1 inhibitors employed prior to facial nerve injury. This, in combination with the current lineage tracing data, will permit further understanding of the role of the Hh pathway in facial nerve injury and recovery.