Hedgehog signaling promotes endoneurial fibroblast migration and Vegf-A expression following facial nerve injury.
Hedgehog signaling promotes endoneurial fibroblast migration and Vegf-A expression following facial nerve injury.
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刺猬信号传导促进面神经损伤后神经内膜成纤维细胞迁移和Vegf-A表达。
DOI：
10.1016/j.brainres.2020.147204
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发表时间：
2021-01-15
期刊：
影响因子：
2.9
通讯作者：
Pepper JP
中科院分区：
文献类型：
--
作者：
Faniku C;Kong W;He L;Zhang M;Lilly G;Pepper JP
周围神经损伤是一种常见的临床问题，可能导致运动或感觉功能永久性丧失。更好地了解导致神经成功再生的信号通路可能有助于发现新的治疗靶点。 Hedgehog (Hh) 信号通路在神经发育和再生中发挥重要作用。在面神经损伤的小鼠模型中，损伤部位和远端神经内的刺猬反应性成纤维细胞数量均增加。然而，这些细胞在面神经再生中的作用尚不完全清楚。我们假设 Hh 通路在面神经损伤后发挥血管生成和促迁移作用。将刺猬通路调节剂应用于从小鼠面神经分离的小鼠神经内成纤维细胞。评估了通路调节对神经内膜成纤维细胞迁移和细胞增殖的影响。通过 qPCR 测定已知 Hedgehog 靶基因和关键血管生成因子 Vegf-A 的基因表达变化。在体内，小鼠接受通路激动剂（SAG21k）治疗，并通过免疫荧光和原位杂交对受损的面神经标本进行分析。通过 SAG21k 处理激活面神经成纤维细胞中的 Hedgehog 通路可增加 Gli1 和 Ptch1 表达、细胞迁移率以及体外 Vegf-A 表达。在体内，通过免疫荧光和原位杂交检测到，Gli1 和 Vegf-A 的表达似乎在损伤后增加，特别是在神经损伤部位和远端神经。此外，面神经横断损伤后，Gli1 转录物与 Vegf-A 共定位。这些发现描述了 Hedgehog 通路通过对神经成纤维细胞的影响介导的血管生成和促迁移作用。鉴于 Vegf-A 在神经再生中的关键作用，调节该通路可能是改善损伤后面神经再生的潜在治疗靶点。
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. 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. 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. 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.
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