Berezovskaya O, Maysinger D, Fedoroff S
Department of Anatomy, University of Saskatchewan, Saskatoon, Canada.
Int J Dev Neurosci. 1995 Jun-Jul;13(3-4):285-99. doi: 10.1016/0736-5748(95)00013-7.
In this study we used op/op mice, which are deficient in the hematopoietic cytokine, colony-stimulating factor 1 (CSF-1), to determine the effect of CSF-1 on neuronal survival and microglial response in injury. In normal mice microglia express the CSF-1 receptor and are primarily regulated by CSF-1, produced mainly by astrocytes. The CSF-1 deficiency in op/op mice results in a depletion in the number of monocytes and macrophages but does not affect the number or morphology of microglia. We produced an ischemic lesion in the cerebral cortex of mice by disrupting the pia-arachnoid blood vessels in a defined area. Using Nissl stain and astrocyte- and microglia-specific antibodies, we determined the number of viable neurons in such injury and the intensity of glial reaction. The cellular response to injury on the operated side of op/op mice was compared to that on the non-operated contralateral side and to the cellular response in similar lesions in CSF-1 producing C3H/HeJ mice. We found that the systemic lack of CSF-1 in op/op mice results in a significant increase in neuron vulnerability to ischemic injury and considerably reduced microglial response to neuron injury. Remedying the CSF-1 deficiency, either by grafting CSF-1 secreting astroglia into the brain or by implanting encapsulated CSF-1 secreting fibroblast-like cells into the peritoneum, partially restores the microglial response to neuron injury and significantly potentiates neuronal survival in cerebral cortex ischemic lesions. Astroglial reaction was approximately the same in the lesions in op/op mice, grafted and implanted op/op mice and C3H/HeJ mice, indicating that CSF-1 modulates microglia, but not the response of astrocytes to injury. The degree of neuronal survival was not correlated to the degree of microglial proliferation and intensity of their reaction. We report some indications that CSF-1, in addition to modulation of microglia, may also act directly on neurons.
在本研究中，我们使用了op/op小鼠（其造血细胞因子集落刺激因子1（CSF-1）缺乏）来确定CSF-1对损伤中神经元存活和小胶质细胞反应的影响。在正常小鼠中，小胶质细胞表达CSF-1受体，并且主要受主要由星形胶质细胞产生的CSF-1调节。op/op小鼠中CSF-1的缺乏导致单核细胞和巨噬细胞数量减少，但不影响小胶质细胞的数量或形态。我们通过破坏特定区域的软脑膜-蛛网膜血管在小鼠大脑皮层制造了一个缺血性损伤。使用尼氏染色以及星形胶质细胞和小胶质细胞特异性抗体，我们确定了此类损伤中存活神经元的数量以及胶质反应的强度。将op/op小鼠手术侧对损伤的细胞反应与未手术的对侧以及产生CSF-1的C3H/HeJ小鼠类似损伤中的细胞反应进行了比较。我们发现op/op小鼠中系统性缺乏CSF-1导致神经元对缺血性损伤的易损性显著增加，并且小胶质细胞对神经元损伤的反应大大降低。通过将分泌CSF-1的星形胶质细胞移植到大脑中或通过将封装的分泌CSF-1的成纤维细胞样细胞植入腹膜来纠正CSF-1缺乏，可部分恢复小胶质细胞对神经元损伤的反应，并显著增强大脑皮层缺血性损伤中神经元的存活。op/op小鼠、移植和植入后的op/op小鼠以及C3H/HeJ小鼠损伤中的星形胶质细胞反应大致相同，表明CSF-1调节小胶质细胞，但不调节星形胶质细胞对损伤的反应。神经元存活程度与小胶质细胞增殖程度及其反应强度无关。我们报告了一些迹象表明，CSF-1除了调节小胶质细胞外，还可能直接作用于神经元。
