Department of Geriatric Medicine, Fujian Provincial Hospital, 134 Dongjie Road, Fuzhou, Fujian, 350001, China.
Provincial Clinical Medical College of Fujian Medical University, 134 Dongjie Road, Fuzhou, Fujian, 350001, China.
Stem Cell Res Ther. 2017 Oct 10;8(1):223. doi: 10.1186/s13287-017-0671-6.
Stem cell transplantation has been documented to promote functional recovery in animal models of stroke; however, the underlying mechanisms are not yet fully understood. As netrin-1 and its receptor deleted in colorectal cancer (DCC) are important regulators in neuronal and vascular activities, the present study attempted to explore whether netrin-1 and DCC are involved in the neuroprotection of stem cell-based therapies in a rat ischemic stroke model.
Adult male Sprague-Dawley rats were subjected to a transient middle cerebral artery occlusion (MCAO) and subsequently received an intra-arterial injection of 2 × 10 PKH26-labeled adipose-derived stem cells (ADSCs) or saline 24 h later. Neurological function was evaluated by behavioral tests before the rats were sacrificed at days 7 and 14 after MCAO. The migration of ADSCs and regeneration of neuronal fibers and blood vessels were determined by immunofluorescence staining. The expression of netrin-1 and DCC was analyzed by Western blot and immunofluorescence staining.
ADSC transplantation significantly improved the neurological recovery at days 7 and 14, and noticeably promoted the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex at day 14. PKH26-labeled ADSCs located mainly in the peri-infarct area at days 7 and 14. In ADSC-treated rats, the expression of netrin-1 and DCC significantly increased in the peri-infarct cortex at days 7 and 14. Immunofluorescence staining showed that netrin-1 was mainly expressed by neuronal perikaryal in the peri-infarct cortex, and DCC was mainly expressed by neuronal fibers and was present around the blood vessels in the peri-infarct cortex.
These findings suggest that ADSC transplantation facilitates the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex and improves neurological functions, which may be attributed, at least in part, to the involvement of upregulated netrin-1 and DCC in the remodeling of neuronal and vascular networks in the peri-infarct cortex.
干细胞移植已被证明可促进中风动物模型的功能恢复；然而，其潜在机制尚未完全阐明。由于轴突导向因子 netrin-1 和其受体Deleted in Colorectal Cancer（DCC）是神经元和血管活动的重要调节因子，本研究试图探讨 netrin-1 和 DCC 是否参与了基于干细胞的治疗在大鼠缺血性中风模型中的神经保护作用。
成年雄性 Sprague-Dawley 大鼠接受短暂性大脑中动脉闭塞（MCAO），并在 MCAO 后 24 小时内进行经动脉注射 2×10PKH26 标记的脂肪来源干细胞（ADSCs）或生理盐水。在 MCAO 后 7 天和 14 天处死大鼠之前，通过行为测试评估神经功能。通过免疫荧光染色测定 ADSC 的迁移和神经元纤维及血管的再生。通过 Western blot 和免疫荧光染色分析 netrin-1 和 DCC 的表达。
ADSC 移植可显著改善 MCAO 后 7 天和 14 天的神经功能恢复，并显著促进梗塞周围皮质神经元纤维和血管的再生。PKH26 标记的 ADSC 主要位于 MCAO 后 7 天和 14 天的梗塞周围区。在 ADSC 治疗的大鼠中，梗塞周围皮质中 netrin-1 和 DCC 的表达在 MCAO 后 7 天和 14 天明显增加。免疫荧光染色显示，netrin-1 主要表达于梗塞周围皮质的神经元胞体，DCC 主要表达于神经元纤维，存在于梗塞周围皮质的血管周围。
这些发现表明，ADSC 移植促进了梗塞周围皮质中神经元纤维和血管的再生，并改善了神经功能，这至少部分归因于上调的 netrin-1 和 DCC 参与了梗塞周围皮质神经元和血管网络的重塑。
