C Faniku1, W Kong2, L He1, M Zhang1, G Lilly3, J P Pepper4. 1. Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. 2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. 3. Department of Otolaryngology-Head and Neck Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, PV01, Portland, OR 97239, USA. 4. Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Division of Facial Plastic & Reconstructive Surgery, Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, 801 Welch Rd, Stanford, CA 94305, USA. Electronic address: jpepper@stanford.edu.
Abstract
BACKGROUND: Peripheral nerve injuries are a common clinical problem which may result in permanent loss of motor or sensory function. A better understanding of the signaling pathways that lead to successful nerve regeneration may help in discovering new therapeutic targets. The Hedgehog (Hh) signaling pathway plays significant roles in nerve development and regeneration. In a mouse model of facial nerve injury, Hedgehog-responsive fibroblasts increase in number both at the site of injury and within the distal nerve. However, the role of these cells in facial nerve regeneration is not fully understood. We hypothesize that the Hh pathway plays an angiogenic and pro-migratory role following facial nerve injury. METHODS: Hedgehog pathway modulators were applied to murine endoneurial fibroblasts isolated from the murine facial nerve. The impact of pathway modulation on endoneurial fibroblast migration and cell proliferation was assessed. Gene expression changes of known Hedgehog target genes and the key angiogenic factor Vegf-A were determined by qPCR. In vivo, mice were treated with pathway agonist (SAG21k) and injured facial nerve specimens were analyzed via immunofluorescence and in situ hybridization. RESULTS: Hedgehog pathway activation in facial nerve fibroblasts via SAG21k treatment increases Gli1 and Ptch1 expression, the rate of cellular migration, and Vegf-A expression in vitro. In vivo, expression of Gli1 and Vegf-A expression appears to increase after injury, particularly at the site of nerve injury and the distal nerve, as detected by immunofluorescence and in situ hybridization. Additionally, Gli1 transcripts co-localize with Vegf-A following transection injury to the facial nerve. DISCUSSION: These findings describe an angiogenic and pro-migratory role for the Hedgehog pathway mediated through effects on nerve fibroblasts. Given the critical role of Vegf-A in nerve regeneration, modulation of this pathway may represent a potential therapeutic target to improve facial nerve regeneration following injury.
BACKGROUND: Peripheral nerve injuries are a common clinical problem which may result in permanent loss of motor or sensory function. A better understanding of the signaling pathways that lead to successful nerve regeneration may help in discovering new therapeutic targets. The Hedgehog (Hh) signaling pathway plays significant roles in nerve development and regeneration. In a mouse model of facial nerve injury, Hedgehog-responsive fibroblasts increase in number both at the site of injury and within the distal nerve. However, the role of these cells in facial nerve regeneration is not fully understood. We hypothesize that the Hh pathway plays an angiogenic and pro-migratory role following facial nerve injury. METHODS: Hedgehog pathway modulators were applied to murine endoneurial fibroblasts isolated from the murine facial nerve. The impact of pathway modulation on endoneurial fibroblast migration and cell proliferation was assessed. Gene expression changes of known Hedgehog target genes and the key angiogenic factor Vegf-A were determined by qPCR. In vivo, mice were treated with pathway agonist (SAG21k) and injured facial nerve specimens were analyzed via immunofluorescence and in situ hybridization. RESULTS: Hedgehog pathway activation in facial nerve fibroblasts via SAG21k treatment increases Gli1 and Ptch1 expression, the rate of cellular migration, and Vegf-A expression in vitro. In vivo, expression of Gli1 and Vegf-A expression appears to increase after injury, particularly at the site of nerve injury and the distal nerve, as detected by immunofluorescence and in situ hybridization. Additionally, Gli1 transcripts co-localize with Vegf-A following transection injury to the facial nerve. DISCUSSION: These findings describe an angiogenic and pro-migratory role for the Hedgehog pathway mediated through effects on nerve fibroblasts. Given the critical role of Vegf-A in nerve regeneration, modulation of this pathway may represent a potential therapeutic target to improve facial nerve regeneration following injury.
Authors: E Parmantier; B Lynn; D Lawson; M Turmaine; S S Namini; L Chakrabarti; A P McMahon; K R Jessen; R Mirsky Journal: Neuron Date: 1999-08 Impact factor: 17.173
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