Ping Suning, Qiu Xuecheng, Gonzalez-Toledo Maria E, Liu Xiaoyun, Zhao Li-Ru
Department of Neurosurgery, State University of New York, Upstate Medical University, Syracuse, NY, United States.
Department of Neurology, Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, United States.
Front Cell Dev Biol. 2021 Jan 12;8:627733. doi: 10.3389/fcell.2020.627733. eCollection 2020.
Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL.
伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是一种由Notch3突变引起的脑小血管疾病，可导致复发性缺血性中风和血管性痴呆。目前尚无能够阻止或延缓CADASIL进展的治疗方法。我们已经证明，在CADASIL的TgNotch3R90C小鼠模型中，联合使用干细胞因子（SCF）和粒细胞集落刺激因子（G-CSF）（SCF+G-CSF）进行治疗，可减少脑小血管血栓形成。然而，SCF+G-CSF治疗是否能保护神经元免受微血管血栓形成引起的缺血性损伤仍不清楚。通过骨髓移植追踪血栓形成，我们观察到22月龄的TgNotch3R90C小鼠的皮质、纹状体和海马中广泛分布着毛细血管血栓形成。然而，毛细血管血栓形成主要发生在皮质。在血栓形成的毛细血管附近区域可见神经元丢失，在有分支的血栓形成的毛细血管相邻区域发现严重的神经元丢失。SCF+G-CSF重复治疗可显著减轻22月龄TgNotch3R90C小鼠皮质血栓形成的毛细血管附近区域的神经元丢失。脑皮质中毛细血管血栓形成导致的神经元丢失可能在CADASIL的发病机制中起关键作用。SCF+G-CSF治疗可改善TgNotch3R90C小鼠中毛细血管血栓形成诱导的缺血性神经元丢失。本研究为理解CADASIL的进展以及SCF+G-CSF在CADASIL微血管缺血情况下的神经保护治疗潜力提供了新的见解。
