人间充质干细胞抑制嗜中性粒细胞凋亡：骨髓壁龛嗜中性粒细胞保存模式

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主题：人间充质干细胞抑制嗜中性粒细胞凋亡：骨髓壁龛嗜中性粒细胞保存模式9 v0 Y2 g  E2 h" V

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$ j; L% j5 K4 @间充质干细胞（MSC）在一个假想的血管周壁龛中与骨髓窦状隙有紧密联系。这些脉管包含一个大的成熟未增殖嗜中性粒细胞贮池。本文我们研究了人骨髓MSC对嗜中性粒细胞生存和效应功能的影响。健康供者来源的MSC，在很低的MSC:嗜中性粒细胞比率（至1：500）下，显著抑制静止和白介素8活化的嗜中性粒细胞的凋亡，并且减弱了氮端甲酰化的甲硫氨酰-亮氨酰-苯丙氨酸(f-MLP)诱导的突发性呼吸。Transwell实验证明：MSC的抗凋亡活性无需细胞间的接触。抗体中和实验证明：活化STAT-3转录因子信号激活的IL6是保护嗜中性粒细胞抗凋亡的关键MSC来源可溶性因子。此外，我们通过实时反转录PCR和酶联免疫实验检测到MSC中IL6的表达。最终，我们发现重组IL6可以防止嗜中性粒细胞凋亡，且这种效应呈现剂量依赖性。MSC对嗜中性粒细胞的吞噬作用、粘附分子表达和（嗜中性粒细胞）对IL8、f-MLP或C5a的趋化作用无影响。这些结果支持以下结论：（a）在骨髓壁龛中，MSC可能保护贮池中的嗜中性粒细胞不凋亡，保留其效应者功能并预防由氧化代谢引起的过度或不恰当活化，以及（b）明确了一种新的分子机制：通过抑制凋亡以及产生不影响吞噬和趋化作用的活性氧簇，来控制活化嗜中性粒细胞的炎性潜能。
+ K0 k2 C' q# [( c) ?原摘要：Mesenchymal stem cells (MSC) establish close interactions with bone marrow sinusoids in a putative perivascular niche. These vessels contain a large storage pool of mature nonproliferating neutrophils. Here, we have investigated the effects of human bone marrow MSC on neutrophil survival and effector functions. MSC from healthy donors, at very low MSC:neutrophil ratios (up to 1:500), significantly inhibited apoptosis of resting and interleukin (IL)-8-activated neutrophils and dampened N-formyl-l-methionin-l-leucyl-l-phenylalanine (f-MLP)-induced respiratory burst. The antiapoptotic activity of MSC did not require cell-to-cell contact, as shown by transwell experiments. Antibody neutralization experiments demonstrated that the key MSC-derived soluble factor responsible for neutrophil protection from apoptosis was IL-6, which signaled by activating STAT-3 transcription factor. Furthermore, IL-6 expression was detected in MSC by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Finally, recombinant IL-6 was found to protect neutrophils from apoptosis in a dose-dependent manner. MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL-8, f-MLP, or C5a. These results support the following conclusions: (a) in the bone marrow niche, MSC likely protect neutrophils of the storage pool from apoptosis, preserving their effector functions and preventing the excessive or inappropriate activation of the oxidative metabolism, and (b) a novel mechanism whereby the inflammatory potential of activated neutrophils is harnessed by inhibition of apoptosis and reactive oxygen species production without impairing phagocytosis and chemotaxis has been identified.
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