Traumatic brain injury (TBI) is a major cause of death and disability in young adults worldwide. TBI-induced long-term cognitive deficits represent a growing clinical problem. Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are involved in neuroprotection and neuronal plasticity. However, the knowledge concerning reparative efficacy of SCF + G-CSF treatment in post-acute TBI recovery remains incomplete. This study aims to determine the efficacy of SCF + G-CSF on post-acute TBI recovery in young adult mice. The controlled cortical impact model of TBI was used for inducing a severe damage in the motor cortex of the right hemisphere in 8-week-old male C57BL mice. SCF + G-CSF treatment was initiated 3 weeks after induction of TBI. Severe TBI led to persistent motor functional deficits (Rota-Rod test) and impaired spatial learning function (water maze test). SCF + G-CSF treatment significantly improved the severe TBI-impaired spatial learning function 6 weeks after treatment. TBI also caused significant increases of Fluoro-Jade C positive degenerating neurons in bilateral frontal cortex, striatum and hippocampus, and significant reductions in MAP2⁺ apical dendrites and overgrowth of SMI312⁺ axons in peri-TBI cavity frontal cortex and in the ipsilateral hippocampal CA1 at 24 weeks post-TBI. SCF + G-CSF treatment significantly reduced TBI-induced neurodegeneration in the contralateral frontal cortex and hippocampal CA1, increased MAP2⁺ apical dendrites in the peri-TBI cavity frontal cortex, and prevented TBI-induced axonal overgrowth in both the peri-TBI cavity frontal cortex and ipsilateral hippocampal CA1.These findings reveal a novel pathology of axonal overgrowth after severe TBI and demonstrate a therapeutic potential of SCF + G-CSF in ameliorating severe TBI-induced long-term neuronal pathology, neurostructural network malformation, and impairments in spatial learning.

创伤性脑损伤 (TBI) 是全球年轻人死亡和残疾的主要原因。TBI 引起的长期认知缺陷代表了一个日益严重的临床问题。干细胞因子 (SCF) 和粒细胞集落刺激因子 (G-CSF) 参与神经保护和神经元可塑性。然而，关于 SCF + G-CSF 治疗在急性 TBI 后恢复中的修复功效的知识仍然不完整。本研究旨在确定 SCF + G-CSF 对年轻成年小鼠急性 TBI 后恢复的疗效。TBI 的受控皮层撞击模型用于诱导 8 周龄雄性 C57BL 小鼠右半球运动皮层的严重损伤。SCF + G-CSF 治疗在 TBI 诱导后 3 周开始。严重的 TBI 导致持续的运动功能缺陷（Rota-Rod 测试）和空间学习功能受损（水迷宫测试）。SCF + G-CSF 治疗在治疗后 6 周显着改善了严重的 TBI 受损空间学习功能。TBI 还引起双侧额叶皮层、纹状体和海马中 Fluoro-Jade C 阳性退化神经元的显着增加，以及 MAP2 的显着减少⁺ TBI 后 24 周，TBI 周腔额叶皮层和同侧海马 CA1中 SMI312 的顶端树突和过度生长⁺轴突。SCF + G-CSF 治疗显着减少了 TBI 诱导的对侧额叶皮层和海马 CA1 的神经变性，增加了 TBI 周围腔额叶皮层中的MAP2 ⁺顶端树突，并防止了 TBI 周围腔额叶中 TBI 诱导的轴突过度生长皮层和同侧海马 CA1。这些发现揭示了严重 TBI 后轴突过度生长的新病理，并证明了 SCF + G-CSF 在改善严重 TBI 诱导的长期神经元病理、神经结构网络畸形和空间学习障碍方面的治疗潜力.