Nagoshi Narihito, Okano Hideyuki
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
J Neurochem. 2017 Jun;141(6):848-860. doi: 10.1111/jnc.13986. Epub 2017 Apr 5.
Numerous basic research studies have suggested the potential efficacy of neural precursor cell (NPC) transplantation in spinal cord injury (SCI). However, in most such studies, the origin of the cells used was mainly fetal tissue or embryonic stem cells, both of which carry potential ethical concerns with respect to clinical use. The development of induced pluripotent stem cells (iPSCs) opened a new path toward regenerative medicine for SCI. iPSCs can be generated from somatic cells by induction of transcription factors, and induced to differentiate into NPCs with characteristics of cells of the central nervous system. The beneficial effect of iPSC-derived NPC transplantation has been reported from our group and others working in rodent and non-human primate models. These promising results facilitate the application of iPSCs for clinical applications in SCI patients. However, iPSCs also have issues, such as genetic/epigenetic abnormalities and tumorigenesis because of the artificial induction method, that must be addressed prior to clinical use. The selection of somatic cells, generation of integration-free iPSCs, and characterization of differentiated NPCs with thorough quality management are all needed to address these potential risks. To enhance the efficacy of the transplanted iPSC-NPCs, especially at chronic phase of SCI, administration of a chondroitinase or semaphorin3A inhibitor represents a potentially important means of promoting axonal regeneration through the lesion site. The combined use of rehabilitation with such cell therapy approaches is also important, as repetitive training enhances neurite outgrowth of transplanted cells and strengthens neural circuits at central pattern generators. Our group has already evaluated clinical grade iPSC-derived NPCs, and we look forward to initiating clinical testing as the next step toward determining whether this approach is safe and effective for clinical use. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".
众多基础研究表明神经前体细胞（NPC）移植在脊髓损伤（SCI）中具有潜在疗效。然而，在大多数此类研究中，所使用细胞的来源主要是胎儿组织或胚胎干细胞，这两者在临床应用方面都存在潜在的伦理问题。诱导多能干细胞（iPSC）的发展为SCI的再生医学开辟了一条新途径。iPSC可通过转录因子诱导从体细胞产生，并被诱导分化为具有中枢神经系统细胞特征的NPC。我们团队及其他研究人员在啮齿动物和非人类灵长类动物模型中报道了iPSC来源的NPC移植的有益效果。这些有前景的结果促进了iPSC在SCI患者临床应用中的应用。然而，由于人工诱导方法，iPSC也存在诸如遗传/表观遗传异常和肿瘤发生等问题，在临床应用前必须加以解决。为解决这些潜在风险，需要选择体细胞、生成无整合的iPSC以及对分化的NPC进行全面质量管理的特性鉴定。为提高移植的iPSC-NPC的疗效，尤其是在SCI的慢性期，施用软骨素酶或信号素3A抑制剂是促进轴突通过损伤部位再生的潜在重要手段。将康复与这种细胞治疗方法联合使用也很重要，因为重复训练可增强移植细胞的神经突生长并加强中枢模式发生器处的神经回路。我们团队已经评估了临床级iPSC来源的NPC，我们期待启动临床试验，作为确定这种方法在临床应用中是否安全有效的下一步。本文是“日本神经化学学会成立60周年”迷你综述系列的一部分。
