Kim Jang Hun, Kang Ho-Young, Lee Jihun, Kim Jong-Hoon, Geum Dongho, Park Dong-Hyuk
Department of Neurosurgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Center of Innovative Cell Therapy and Research, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Tissue Eng Regen Med. 2025 Apr;22(3):339-349. doi: 10.1007/s13770-025-00706-z. Epub 2025 Feb 14.
Cell replacement therapy is the only treatment that restores or repairs the function of impaired tissues in neurodegenerative diseases, including vascular dementia (VaD); however, current VaD treatments focus on slowing or mitigating the underlying small vessel disease progression. We aimed to verify the improvement in neurocognition after administering human-induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from in a VaD animal model.
After anesthesia, 10-12-week-old male C5BL/6 mice underwent sham or bilateral carotid artery stenosis (BCAS) surgeries. For BCAS, 0.18-mm micro-coils were wound around the bilateral common carotid arteries to induce chronic vascular insufficiency in the global brain. One day after surgery, the mice were administered phosphate buffer solution or NPC from hiPSCs via the tail vein for 15 d, and divided into sham (n = 6), VEH (n = 6), and NPC (n = 7) groups. Three months after the surgery, neurobehavioral tests including the Y-maze test (YMT), passive avoidance test (PAT), and novel object recognition test (NORT) were performed. Finally, mice brains were sectioned for evaluating microglia (Iba-1), astrocyte (GFAP) activation, and myelin (MBP) degeneration through immunohistochemistry (IHC).
PAT latency (p = 0.01) and discrimination index in the NORT (p = 0.043) increased considerably in the NPC group than in the VEH group. However, alterations in YMT were not considerably higher in the NPC group than in the VEH group (p = 0.65). IHC tests revealed that the GFAP- and IBA-1-positive cell number was remarkably lower in the NPC group than in the VEH group (p < 0.05). Moreover, MBP density was higher in the NPC group.
hiPSC-derived NPCs have therapeutic potential in cerebral hypoperfusion VaD mice; it improves the working memory of VaD animals by diminishing inflammatory reactions and protecting them from demyelination.
细胞替代疗法是恢复或修复神经退行性疾病（包括血管性痴呆（VaD））中受损组织功能的唯一治疗方法；然而，目前VaD的治疗重点是减缓或减轻潜在的小血管疾病进展。我们旨在验证在VaD动物模型中给予人诱导多能干细胞（hiPSC）来源的神经祖细胞（NPCs）后神经认知功能的改善情况。
麻醉后，对10 - 12周龄的雄性C5BL/6小鼠进行假手术或双侧颈动脉狭窄（BCAS）手术。对于BCAS，将0.18毫米的微线圈缠绕在双侧颈总动脉周围，以诱导全脑慢性血管功能不全。手术后一天，通过尾静脉给小鼠注射磷酸盐缓冲溶液或hiPSC来源的NPCs，持续15天，并分为假手术组（n = 6）、载体组（n = 6）和NPC组（n = 7）。手术后三个月，进行包括Y迷宫试验（YMT）、被动回避试验（PAT）和新物体识别试验（NORT）在内的神经行为测试。最后，对小鼠大脑进行切片，通过免疫组织化学（IHC）评估小胶质细胞（Iba - 1）、星形胶质细胞（GFAP）激活和髓鞘（MBP）变性情况。
与载体组相比，NPC组的PAT潜伏期（p = 0.01）和NORT中的辨别指数（p = 0.043）显著增加。然而，NPC组YMT的变化并不比载体组显著更高（p = 0.65）。免疫组织化学测试显示，NPC组中GFAP和IBA - 1阳性细胞数量明显低于载体组（p < 0.05）。此外，NPC组的MBP密度更高。
hiPSC来源的NPCs对脑灌注不足的VaD小鼠具有治疗潜力；它通过减少炎症反应和保护它们免受脱髓鞘作用来改善VaD动物的工作记忆。
