Chronic pain induces nociceptive neurogenesis in dorsal root ganglia from Sox2-positive satellite cells
Chronic pain induces nociceptive neurogenesis in dorsal root ganglia from Sox2-positive satellite cells
复制标题
慢性疼痛诱导 Sox2 阳性卫星细胞背根神经节发生伤害性神经发生
作者：
Li Zhang;Rougang Xie;Jiping Yang;Youyi Zhao;Chuchu Qi;Ganlan Bian;Mengmeng Wang;Junjia Shan;Chen Wang;Dong Wang;Ceng Luo;Yazhou Wang;Shengxi Wu
慢性疼痛是世界上最常见的慢性病之一。背根神经节(DRG)内感觉神经元的可塑性变化作为其潜在的外周机制已被广泛研究。最近的研究表明，作为DRG中主要的神经胶质细胞，卫星细胞在慢性疼痛的发生/调节中也起着重要的作用。在病理条件下，DRG卫星神经胶质细胞是否会像肠神经节和颈动脉体中的相应细胞那样产生新的神经元，目前还缺乏研究。在这里，我们报告慢性疼痛诱导性别决定区域Y盒2(SOX2)和血小板衍生生长因子受体α(PDGFRα)阳性卫星神经胶质细胞的增殖和祖细胞标志物的上调。BrdU掺入实验显示损伤同侧背根神经节有IB4和CGRP阳性神经元的产生，但无NF200阳性神经元的产生。遗传命运追踪显示，PDGFRα阳性细胞不产生神经元，而Sox2阳性细胞同时产生IB4和CGRP阳性神经元。有趣的是，胶质纤维酸性蛋白阳性细胞是SOX2阳性卫星的一个亚群，只产生IB4阳性神经元。局部持续向坐骨神经干注射河豚毒素可显著减少疼痛诱导的神经再生。此外，膜片钳研究表明，这些胶质细胞衍生的新神经元可以激发动作电位，并对辣椒素做出反应。综上所述，我们的数据显示慢性疼痛诱导的背根节伤害性神经发生来自SOX2阳性卫星细胞，提示DRG神经发生可能在慢性疼痛的病理过程中起作用。
Chronic pain is one of the most prevalent chronic diseases in the world. The plastic changes of sensory neurons in dorsal root ganglia (DRG) have been extensively studied as the underlying periphery mechanism. Recent studies revealed that satellite cells, the major glial cells in DRG, also played important roles in the development/modulation of chronic pain. Whether DRG satellite glial cells generate new neurons as their counterparts in enteric nerve ganglia and carotid body do under pathological conditions remains poorly investigated. Here, we report that chronic pain induces proliferation and upregulation of progenitor markers in the sex‐determining region Y‐box 2 (Sox2)‐ and platelet‐derived growth factor receptor alpha (PDGFRα)‐positive satellite glial cells. BrdU incorporation assay revealed the generation of IB4‐ and CGRP‐positive neurons, but not NF200‐positive neurons in DRG ipsilateral to injury. Genetic fate tracings showed that PDGFRα‐positive cells did not generate neurons, whereas Sox2‐positive cells produced both IB4‐ and CGRP‐positive neurons. Interestingly, glial fibrillary acidic protein‐positive cells, a subpopulation of Sox2‐positive satellites, only gave birth to IB4‐positive neurons. Local persistent delivery of tetrodotoxin to the sciatic nerve trunk significantly reduced the pain‐induced neurogenesis. Furthermore, patch‐clamp studies demonstrated that these glia‐derived new neurons could fire action potentials and respond to capsaicin. Taken together, our data demonstrated a chronic pain‐induced nociceptive neurogenesis in DRG from Sox2‐positive satellite cells, indicating a possible contribution of DRG neurogenesis to the pathology of chronic pain.