Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury.
Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury.
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DOI：
10.1186/jbiol85
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发表时间：
2008-09-19
影响因子：
--
通讯作者：
Davies SJ
中科院分区：
文献类型：
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作者：
Davies JE;Pröschel C;Zhang N;Noble M;Mayer-Pröschel M;Davies SJ
开发针对受伤或患病组织的细胞移植疗法的两个关键挑战是确定最佳细胞和有害的副作用。这在脊髓损伤的情况下尤其值得关注，最近的研究表明移植的神经上皮干细胞可以产生疼痛综合征。我们之前已经证明，用骨形态发生蛋白-4（BMP-4）处理的胶质限制性前体细胞（GRP）衍生的星形胶质细胞在移植到大鼠脊髓损伤后可以促进强健的轴突再生和功能恢复。相比之下，我们现在表明，通过暴露于 gp130 激动剂睫状神经营养因子（GDAsCNTF）（参与星形发生的另一个主要信号通路）产生的 GRP 衍生星形胶质细胞（GDA）的移植，会导致轴突再生和功能恢复失败。此外，GDACNTF细胞的移植促进了损伤后2周机械异常性疼痛和热痛觉过敏的发生，这种效应持续到损伤后5周。类似神经性疼痛的延迟发作也是由未分化的 GRP 移植引起的。相比之下，移植 GDAsBMP 的大鼠没有表现出疼痛综合征。我们的结果表明，并非所有源自胚胎前体的星形胶质细胞都同样有益于脊髓修复，并且它们首次鉴定了一种分化的神经细胞类型，该神经细胞类型在移植到受损脊髓时可引起疼痛综合征，强调了在开始临床试验之前评估候选细胞引起异常性疼痛的能力的重要性。他们还证实了用骨形态发生蛋白治疗的 GDA 在修复脊髓损伤方面的特殊前景。
Two critical challenges in developing cell-transplantation therapies for injured or diseased tissues are to identify optimal cells and harmful side effects. This is of particular concern in the case of spinal cord injury, where recent studies have shown that transplanted neuroepithelial stem cells can generate pain syndromes. We have previously shown that astrocytes derived from glial-restricted precursor cells (GRPs) treated with bone morphogenetic protein-4 (BMP-4) can promote robust axon regeneration and functional recovery when transplanted into rat spinal cord injuries. In contrast, we now show that transplantation of GRP-derived astrocytes (GDAs) generated by exposure to the gp130 agonist ciliary neurotrophic factor (GDAsCNTF), the other major signaling pathway involved in astrogenesis, results in failure of axon regeneration and functional recovery. Moreover, transplantation of GDACNTF cells promoted the onset of mechanical allodynia and thermal hyperalgesia at 2 weeks after injury, an effect that persisted through 5 weeks post-injury. Delayed onset of similar neuropathic pain was also caused by transplantation of undifferentiated GRPs. In contrast, rats transplanted with GDAsBMP did not exhibit pain syndromes. Our results show that not all astrocytes derived from embryonic precursors are equally beneficial for spinal cord repair and they provide the first identification of a differentiated neural cell type that can cause pain syndromes on transplantation into the damaged spinal cord, emphasizing the importance of evaluating the capacity of candidate cells to cause allodynia before initiating clinical trials. They also confirm the particular promise of GDAs treated with bone morphogenetic protein for spinal cord injury repair.