Biochemistry and Molecular Biology Unit, School of Medicine, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
Glia. 2014 Feb;62(2):247-58. doi: 10.1002/glia.22603. Epub 2013 Dec 6.
Microglia positively affect neural progenitor cell physiology through the release of inflammatory mediators or trophic factors. We demonstrated previously that reactive microglia foster K(ATP) -channel expression and that blocking this channel using glibenclamide administration enhances striatal neurogenesis after stroke. In this study, we investigated whether the microglial K(ATP) -channel directly influences the activation of neural precursor cells (NPCs) from the subventricular zone using transgenic Csf1r-GFP mice. In vitro exposure of NPCs to lipopolysaccharide and interferon-gamma resulted in a significant decrease in precursor cell number. The complete removal of microglia from the culture or exposure to enriched microglia culture also decreased the precursor cell number. The addition of glibenclamide rescued the negative effects of enriched microglia on neurosphere formation and promoted a ∼20% improvement in precursor cell number. Similar results were found using microglial-conditioned media from isolated microglia. Using primary mixed glial and pure microglial cultures, glibenclamide specifically targeted reactive microglia to restore neurogenesis and increased the microglial production of the chemokine monocyte chemoattractant protein-1 (MCP-1). These findings provide the first direct evidence that the microglial K(ATP) -channel is a regulator of the proliferation of NPCs under inflammatory conditions.
小胶质细胞通过释放炎症介质或营养因子积极影响神经祖细胞的生理机能。我们之前曾证明反应性小胶质细胞促进 K(ATP) 通道的表达，并且使用格列本脲给药阻断该通道可增强中风后的纹状体神经发生。在这项研究中，我们使用 Csf1r-GFP 转基因小鼠研究了小胶质细胞 K(ATP) 通道是否直接影响来自侧脑室下区的神经前体细胞（NPC）的激活。体外将 NPC 暴露于脂多糖和干扰素-γ中会导致前体细胞数量显著减少。从培养物中完全去除小胶质细胞或暴露于富含小胶质细胞的培养物也会减少前体细胞数量。格列本脲的添加挽救了富含小胶质细胞对神经球形成的负面影响，并促进了前体细胞数量约 20%的改善。从小胶质细胞分离培养物的小胶质细胞条件培养基中也发现了类似的结果。使用原代混合神经胶质和纯小胶质细胞培养物，格列本脲特异性靶向反应性小胶质细胞以恢复神经发生，并增加趋化因子单核细胞趋化蛋白-1（MCP-1）的小胶质细胞产生。这些发现提供了第一个直接证据，表明小胶质细胞 K(ATP) 通道是炎症条件下 NPC 增殖的调节剂。
