Stem Cell Reviews and Reports ( IF 4.5 ) Pub Date : 2021-01-03 , DOI: 10.1007/s12015-020-10102-w Dongyan Wang 1 , Junhou Lu 1 , Xiaojing Xu 1 , Ye Yuan 1 , Yu Zhang 2 , Jianwei Xu 3 , Huanhuan Chen 1 , Jinming Liu 1 , Yixin Shen 2 , Huanxiang Zhang 1
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Dorsal root ganglia (DRG) sensory neurons can transmit information about noxious stimulus to cerebral cortex via spinal cord, and play an important role in the pain pathway. Alterations of the pain pathway lead to CIPA (congenital insensitivity to pain with anhidrosis) or chronic pain. Accumulating evidence demonstrates that nerve damage leads to the regeneration of neurons in DRG, which may contribute to pain modulation in feedback. Therefore, exploring the regeneration process of DRG neurons would provide a new understanding to the persistent pathological stimulation and contribute to reshape the somatosensory function. It has been reported that a subpopulation of satellite glial cells (SGCs) express Nestin and p75, and could differentiate into glial cells and neurons, suggesting that SGCs may have differentiation plasticity. Our results in the present study show that DRG-derived SGCs (DRG-SGCs) highly express neural crest cell markers Nestin, Sox2, Sox10, and p75, and differentiate into nociceptive sensory neurons in the presence of histone deacetylase inhibitor VPA, Wnt pathway activator CHIR99021, Notch pathway inhibitor RO4929097, and FGF pathway inhibitor SU5402. The nociceptive sensory neurons express multiple functionally-related genes (SCN9A, SCN10A, SP, Trpv1, and TrpA1) and are able to generate action potentials and voltage-gated Na+ currents. Moreover, we found that these cells exhibited rapid calcium transients in response to capsaicin through binding to the Trpv1 vanilloid receptor, confirming that the DRG-SGC-derived cells are nociceptive sensory neurons. Further, we show that Wnt signaling promotes the differentiation of DRG-SGCs into nociceptive sensory neurons by regulating the expression of specific transcription factor Runx1, while Notch and FGF signaling pathways are involved in the expression of SCN9A. These results demonstrate that DRG-SGCs have stem cell characteristics and can efficiently differentiate into functional nociceptive sensory neurons, shedding light on the clinical treatment of sensory neuron-related diseases.
Graphical Abstract
中文翻译：
卫星神经胶质细胞产生伤害性感觉神经元
背根神经节（DRG）感觉神经元可以通过脊髓将有害刺激信息传递到大脑皮层，在疼痛通路中发挥重要作用。疼痛通路的改变导致 CIPA（先天性对无汗疼痛不敏感）或慢性疼痛。越来越多的证据表明，神经损伤导致 DRG 中神经元的再生，这可能有助于反馈中的疼痛调节。因此，探索DRG神经元的再生过程，将为持续性病理刺激提供新的认识，有助于重塑体感功能。据报道，卫星神经胶质细胞（SGCs）的一个亚群表达Nestin和p75，并且可以分化为神经胶质细胞和神经元，表明SGCs可能具有分化可塑性。我们在本研究中的结果表明，DRG 衍生的 SGC (DRG-SGC) 高度表达神经嵴细胞标志物 Nestin、Sox2、Sox10 和 p75，并在组蛋白去乙酰化酶抑制剂 VPA、Wnt 通路激活剂存在下分化为伤害性感觉神经元CHIR99021、Notch 通路抑制剂 RO4929097 和 FGF 通路抑制剂 SU5402。伤害性感觉神经元表达多种功能相关基因（SCN9A、SCN10A、SP、Trpv1 和 TrpA1），并能够产生动作电位和电压门控 Na+电流。此外，我们发现这些细胞通过与 Trpv1 vanilloid 受体结合而对辣椒素产生快速的钙瞬变，这证实了 DRG-SGC 衍生的细胞是伤害性感觉神经元。此外，我们表明 Wnt 信号通过调节特定转录因子 Runx1 的表达促进 DRG-SGC 分化为伤害性感觉神经元，而 Notch 和 FGF 信号通路参与 SCN9A 的表达。这些结果表明，DRG-SGCs具有干细胞特性，可有效分化为功能性伤害性感觉神经元，为临床治疗感觉神经元相关疾病提供了启示。
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