Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells
Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells
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DOI：
10.1161/circulationaha.105.563668
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发表时间：
2006-02-07
期刊：
影响因子：
37.8
通讯作者：
Hotta, T
中科院分区：
文献类型：
--
作者：
Kawada, H;Takizawa, S;Hotta, T
造血细胞因子、粒细胞集落刺激因子（G-CSF）和干细胞因子（SCF）被报道具有神经保护作用或支持神经发生。这些细胞因子还动员骨髓（BM）细胞进入脑，并且BM衍生的细胞分化成神经元细胞。我们管理局灶性脑缺血后，这些造血细胞因子，并评估其影响和治疗的时间窗neuronal regeneration.Methods和Results -我们诱导永久性大脑中动脉闭塞的小鼠，其BM已被替换为BM细胞从绿色荧光蛋白（GFP）转基因小鼠。在急性期（第1 ~ 10天）和亚急性期（第11 ~ 20天）分别给予G-CSF和SCF治疗，观察脑功能和组织学变化。另外，我们在细胞因子治疗期间注射溴脱氧尿苷以评估脑中的细胞动力学。每个实验组制备6只小鼠。与急性期治疗相比，在亚急性期给予G-CSF和SCF不仅有效地改善了运动表现，而且改善了脑功能。急性期和亚急性期治疗相对于载体治疗相同地减少梗塞体积。然而，亚急性期治疗显著诱导BM衍生的神经元细胞过渡到梗死周围区域，并刺激神经增殖区内在神经干/祖细胞的增殖。增强细胞因子诱导的BM衍生细胞和内在神经干/祖细胞的神经元细胞生成。由于G-CSF和SCF可用于临床，这些发现提示了一种新的治疗中风的策略。
Background - Hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) were reported to show a neuroprotective effect or to support neurogenesis. These cytokines also mobilize bone marrow (BM) cells into the brain, and the BM-derived cells differentiate into neuronal cells. We administered these hematopoietic cytokines after focal cerebral ischemia and assessed their effects and the therapeutic time window for neuronal regeneration.Methods and Results - We induced permanent middle cerebral artery occlusion in mice whose BM had been replaced with BM cells from green fluorescent protein (GFP)-transgenic mice. The occluded mice were treated with G-CSF and SCF in the acute phase (days 1 to 10) or subacute phase (days 11 to 20), and the brain functions and histological changes were evaluated. Separately, we injected bromodeoxyuridine during cytokine treatment to assess cell kinetics in the brain. Six mice were prepared for each experimental group. Administration of G-CSF and SCF in the subacute phase effectively improved not only motor performance but also higher brain function, compared with acute-phase treatment. Acute-phase and subacute-phase treatments identically reduced the infarct volume relative to vehicle treatment. However, subacute-phase treatment significantly induced transition of BM-derived neuronal cells into the peri-infarct area and stimulated proliferation of intrinsic neural stem/progenitor cells in the neuroproliferative zone.Conclusions - Administration of G-CSF and SCF in the subacute phase after focal cerebral ischemia is effective for functional recovery, enhancing cytokine-induced generation of neuronal cells from both BM-derived cells and intrinsic neural stem/progenitor cells. Because G-CSF and SCF are available for clinical use, these findings suggest a new therapeutic strategy for stroke.