Department of Pediatrics, The Sixth Medical Center of PLA General Hospital, Beijing, China, 100048; Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China, 226001.
Department of Pediatrics, The Sixth Medical Center of PLA General Hospital, Beijing, China, 100048.
Cytotherapy. 2024 Dec;26(12):1491-1504. doi: 10.1016/j.jcyt.2024.07.012. Epub 2024 Jul 24.
Cerebral palsy (CP) is the most common physical disability in children, yet lacks an ideal animal model or effective treatment. This study aimed to develop a reliable CP model in neonatal rats and explore the effectiveness and underlying mechanisms of human neural stem cells (hNSCs) transplantation during the sequelae phase of CP.
Vasoconstrictor endothelin-1 (ET-1) was administered intracranially to the motor cortex and striatum of rats on postnatal day 5 to establish a CP model. hNSCs (5 × 10/5 μL) pretreated with hypoxia (5% O for 24 h) were transplanted near the infarct 3 weeks after ET-1 injury (the sequelae phase). The distribution and differentiation of hNSCs were observed after transplantation. Changes in neurotrophic factors, neurogenesis, angiogenesis, axonal plasticity, and motor function were analyzed.
Neurobehavioral tests showed poor muscle strength and postural control in young ET-1 rats. Motor deficits of the left forelimb and gait abnormalities persisted into adulthood. Histopathological findings and MRI indicated the atrophy of the cortex, striatum, and adjacent corpus callosum in ET-1 rats. At 56 days after transplantation, hNSCs were widely distributed in the ipsilateral hemisphere, and differentiated into neurons, oligodendrocytes and astrocytes. Transplantation of hNSCs increased BDNF and VEGF expression, EdU cell number in the SVZ area, RECA-1 vessel density and GAP-43 intensity around the lesion in ET-1 rats. The cylinder test revealed a significant increase in the left forelimb motor function from 28 days after transplantation, and the staircase and CatWalk tests showed improvements in fine motor function and gait parameters.
Intracerebral injection of ET-1 modelled key functional and histopathological features of CP. hNSCs transplanted during the sequelae phase of CP resulted in long-term improvement in motor performance, possibly attributed to its capacity to stimulate neurotrophic factors, facilitate neurogenesis, angiogenesis, and promote axonal plasticity.
脑瘫（CP）是儿童中最常见的身体残疾，但缺乏理想的动物模型或有效的治疗方法。本研究旨在建立一种新的新生大鼠 CP 模型，并探讨人神经干细胞（hNSC）移植在 CP 后遗症期的有效性及其潜在机制。
在新生大鼠出生后第 5 天，通过向大脑皮质和纹状体颅内注射血管收缩剂内皮素-1（ET-1）建立 CP 模型。将 hNSC（5×10/5μL）在 ET-1 损伤后 3 周（后遗症期）进行缺氧预处理（5%O2 24h），然后在梗死灶附近移植。移植后观察 hNSC 的分布和分化。分析神经营养因子、神经发生、血管生成、轴突可塑性和运动功能的变化。
神经行为学测试显示，ET-1 幼鼠肌肉力量和姿势控制较差。左侧前肢运动缺陷和步态异常持续到成年期。组织病理学发现和 MRI 显示 ET-1 大鼠皮质、纹状体和相邻胼胝体萎缩。移植后 56 天，hNSC 广泛分布于左侧半球，分化为神经元、少突胶质细胞和星形胶质细胞。hNSC 移植可增加 ET-1 大鼠 SVZ 区 BDNF 和 VEGF 表达、EdU 细胞数量、RECAl 血管密度和损伤周围 GAP-43 强度。从移植后 28 天开始，圆筒试验显示左侧前肢运动功能明显改善，阶梯试验和 CatWalk 试验显示精细运动功能和步态参数改善。
脑内注射 ET-1 可模拟 CP 的关键功能和组织病理学特征。CP 后遗症期移植 hNSC 可长期改善运动功能，可能与其刺激神经营养因子、促进神经发生、血管生成和促进轴突可塑性的能力有关。
