Andreeva Elena R, Udartseva Olga O, Zhidkova Olga V, Buravkov Sergey V, Ezdakova Maria I, Buravkova Ludmila B
Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, Russia.
Faculty of Basic Medicine, Moscow State University, Moscow, Russia.
J Cell Physiol. 2018 Feb;233(2):1535-1547. doi: 10.1002/jcp.26046. Epub 2017 Aug 11.
Multipotent mesenchymal stromal cells (MSCs) are considered cue regulators of tissue remodeling. Their activity is strongly governed by local milieu, where O level is most important. The elevation of inflammatory mediators and acute O lowering may additionally modulate MSC activity. In present paper the priming effects of IFN-gamma on adipose tissue-derived MSCs (ASCs) at tissue-related O level (5%) and acute hypoxic stress (0.1% O ) were assessed as alterations of ASCs' CFU-F, proliferation, migration, osteo-commitment. IFN-gamma priming provoked ROS elevation, cell growth slowdown, attenuation of both spontaneous and induced osteodifferentiation of tissue O -adapted ASCs. The prominent changes in ASC cytoskeleton-related gene transcription was detected. IFN-gamma exposure shifted the ASC paracrine profile, suppressing the production of VEGF and IL-8, while MCP-1 and IL-6 were stimulated. Conditioned medium of IFN-gamma-primed ASCs did not activate vessel growth in the CAM assay, but induced endothelial cell migration in "wound closure." Short-term hypoxia suppressed CFU-F number, IFN-gamma-induced elevation of IL-6 and endothelial cell migration, while it abolished IFN-gamma-provoked VEGF inhibition. After N-acetyl cysteine treatment ROS level was partly abolished providing additional enhancement of IL-6 and suppression of IL-8 and VEGF production. These findings demonstrated that paracrine activity of ASCs in part may be governed by ROS level. Thus, this study first demonstrated that IFN-gamma priming itself and in combination with acute O deprivation could supply dual effects on ASC functions providing both stimulatory and hampering effects. The equilibrium of these factors is a substantial requirement for the execution of MSC remodeling functions.
多能间充质基质细胞（MSCs）被认为是组织重塑的关键调节因子。它们的活性受到局部微环境的强烈调控，其中氧水平最为重要。炎症介质的升高和急性氧降低可能会进一步调节MSCs的活性。在本文中，研究了在组织相关氧水平（5%）和急性低氧应激（0.1% O₂）下，干扰素-γ对脂肪组织来源的间充质干细胞（ASCs）的预处理作用，评估指标包括ASCs的集落形成单位-成纤维细胞（CFU-F）、增殖、迁移和骨定向分化。干扰素-γ预处理引发活性氧（ROS）升高、细胞生长减缓，以及组织氧适应的ASCs自发和诱导性骨分化的减弱。检测到ASCs细胞骨架相关基因转录的显著变化。干扰素-γ暴露改变了ASCs的旁分泌谱，抑制血管内皮生长因子（VEGF）和白细胞介素-8（IL-8）的产生，同时刺激单核细胞趋化蛋白-1（MCP-1）和白细胞介素-6（IL-6）的产生。干扰素-γ预处理的ASCs条件培养基在鸡胚绒毛尿囊膜（CAM）试验中未激活血管生长，但在“伤口愈合”试验中诱导了内皮细胞迁移。短期低氧抑制了CFU-F数量、干扰素-γ诱导的IL-6升高和内皮细胞迁移，同时消除了干扰素-γ引起的VEGF抑制。N-乙酰半胱氨酸处理后，ROS水平部分恢复，进一步增强了IL-6的产生，并抑制了IL-8和VEGF的产生。这些发现表明，ASCs的旁分泌活性部分可能受ROS水平调控。因此，本研究首次证明，干扰素-γ预处理本身以及与急性氧剥夺联合使用，可对ASCs功能产生双重影响，既有刺激作用又有阻碍作用。这些因素的平衡是MSCs执行重塑功能的重要条件。
