Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
Sci Rep. 2017 May 16;7(1):1943. doi: 10.1038/s41598-017-02137-w.
Induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs) are a promising source of tailor-made cell therapy for neurological diseases. However, major obstacles to clinical use still exist. To circumvent complications related to intracerebral administration, we implanted human iPSC-NPCs epidurally over the peri-infarct cortex 7 days after permanent middle cerebral artery occlusion in adult rats. Compared to controls, cell-treated rats showed significant improvements in paretic forelimb usage and grip strength from 10 days post-transplantation (dpt) onwards, as well as reductions in lesion volumes, inflammatory infiltration and astrogliosis at 21 dpt. Few iPSC-NPCs migrated into rat peri-infarct cortices and exhibited poor survival in tissue. To examine the paracrine therapeutic mechanisms of epidural iPSC-NPC grafts, we used transmembrane co-cultures of human iPSC-NPCs with rat cortical cells subjected to oxygen-glucose deprivation. Compared to other human stem cells, iPSC-NPCs were superior at promoting neuronal survival and outgrowth, and mitigating astrogliosis. Using comparative whole-genome microarrays and cytokine neutralization, we identified a neurorestorative secretome from iPSC-NPCs, and neutralizing enriched cytokines abolished neuroprotective effects in co-cultures. This proof-of-concept study demonstrates a relatively safe, yet effective epidural route for delivering human iPSC-NPCs, which acts predominately through discrete paracrine effects to promote functional recovery after stroke.
诱导多能干细胞衍生的神经祖细胞（iPSC-NPCs）是一种有前途的针对神经疾病的定制化细胞疗法的来源。然而，其临床应用仍存在重大障碍。为了避免与脑内给药相关的并发症，我们在成年大鼠永久性大脑中动脉闭塞后 7 天，将人 iPSC-NPC 硬膜外植入梗死周围皮层。与对照组相比，细胞治疗组大鼠从移植后 10 天（dpt）开始，瘫痪前肢的使用和握力明显改善，并且在 21 dpt 时，病灶体积、炎症浸润和星形胶质增生减少。很少有 iPSC-NPC 迁移到大鼠梗死周围皮层，在组织中生存能力差。为了研究硬膜外 iPSC-NPC 移植物的旁分泌治疗机制，我们使用人类 iPSC-NPC 与经历氧葡萄糖剥夺的大鼠皮质细胞的跨膜共培养物。与其他人类干细胞相比，iPSC-NPC 更擅长促进神经元存活和生长，并减轻星形胶质增生。通过比较全基因组微阵列和细胞因子中和，我们从 iPSC-NPC 中鉴定出一个具有神经修复作用的分泌组，并且中和富集的细胞因子可消除共培养物中的神经保护作用。这项概念验证研究表明，硬膜外途径是一种相对安全但有效的递送人 iPSC-NPC 的方法，主要通过离散的旁分泌作用来促进中风后的功能恢复。
