诱导型多能干细胞移植治疗脊髓损伤性神经疼痛及其对Neuregulin-1/ErbB信号通路的研究

Chronic neuropathic pain is a common and debilitating problem following spinal cord injury (SCI). Current clinical therapies for Chronic neuropathic pain are limited. During the last two decades, the search for new therapies has been revolutionized by the discovery of stem cells. Previous studies have demonstrated that transplantation of embryonic stem (ES) cells promotes functional recovery after SCI by promoting ES cells to differentiate into oligodendrocytes and producing myelination after spinal transplantation. This could be associated with Neuregulin-1 (NRG1)/ErbB signaling。However, ESC therapy for human application in the clinic has been hindered by both technical and ethical issues. The recent discovery of induced pluripotent stem (iPS) cells, which allows the ethical issues and immunological rejection associated with embryonic stem (ES) cells to be avoided, provides new prospects for cell replacement strategies in human diseases..In this research plan, we will investigate the effect of spinal transplantation of iPS cell-derived oligodendrocyte progenitor cells (iPSC-OPCs) on SCI-induced chronic neuropathic pain in rats and explore underlying NRG1/ErbB signaling mechanisms. The result will help optimize iPS cell transplantation strategies in the treatment of SCI-induced neuropathic pain and provide experimental evidence to demonstrate the mechanisms by which spinally transplanted stem cells relieve SCI pain. This research is significant in its impact on neuroscience and its potential clinical applications.

慢性神经性疼痛是脊髓损伤后一种常见的并发症，是临床治疗面临的难题。由于干细胞的发现使得对其治疗有了变革性的改变。研究显示，胚胎干细胞移植后可通分化为少突胶质细胞，形成髓鞘,促进功能改善，缓解疼痛。这种作用可能与神经调节蛋白1 / ErbB信号相关。然而，胚胎干细胞用于治疗人类疾病受到了免疫排斥和伦理学问题的限制。诱导型多能干细胞的技术的出现使人们从胚胎干细胞的伦理学争论中解脱出来，也避免了与胚胎干细胞相关免疫排斥问题。对研究应用细胞移植治疗人类疾病带来了新的希望。在本研究计划中，我们将研究脊髓移植诱导型多能干细胞源性少突胶质前体细胞对大鼠脊髓损伤所至的神经性疼痛的治疗效果，并探讨其潜在的神经调节蛋白1 /ErbB 信号通路的作用机理。该项目研究结果将为临床发展诱导型多能干细胞移植治疗脊髓损伤所至的慢性神经疼痛提供分子机理的依据，具有重要的科学意义和临床应用价值。

慢性神经性疼痛是脊髓损伤后一种常见的并发症，是临床治疗面临的难题。由于干细胞的发现使得对其治疗有了变革性的改变。研究显示，胚胎干细胞移植后可分化为少突胶质细胞，形成髓鞘，促进功能改善，缓解疼痛。然而，胚胎干细胞用于治疗人类疾病受到了免疫排斥和伦理学问题的限制。诱导型多能干细胞的技术的出现使人们从胚胎干细胞的伦理学争论中解脱出来，也避免了与胚胎干细胞相关免疫排斥问题。对研究应用细胞移植治疗人类疾病带来了新的希望。在本研究中，我们培养小鼠iPS细胞，将其成功诱导成iPSC-OPCs 细胞，对脊髓钝挫伤性（SCC）大鼠进行损伤局部移植，通过机械疼痛实验对其疼痛行为进行评估；并通过Basso, Beattie, and Bresnahan （BBB）评分对其运动功能进行检测，观察到iPSC-OPCs能够改善SCC大鼠的运动功能，减轻疼痛。通过siRNA干扰实验证实iPSC-OPCs移植主要通过促进髓鞘形成，抑制异常性出芽发挥改善运动功能，减轻异常性疼痛的作用。SCC后神经调节蛋白1/ErbB的表达下调，而给予iPSC-OPC后，其表达增加；通过siRNA干扰技术，证实iPSC-OPC移植发挥促进髓鞘形成、减轻疼痛，是通过神经调节蛋白1/ErbB发挥作用。本研究证实了脊髓移植诱导型多能干细胞源性少突胶质前体细胞能够改善大鼠脊髓损伤所致的神经性疼痛，主要是通过神经调节蛋白1 /ErbB 信号通路发挥作用。该项目研究结果为临床发展诱导型多能干细胞移植治疗脊髓损伤所致的慢性神经疼痛提供分子机理的依据，具有重要的科学意义和临床应用价值。