Liu Liu, He Yi Ren, Liu Shao Jun, Hu Lei, Liang Li Chuang, Liu Dong Liang, Liu Lin, Zhu Zhi Qiang
Department of General Surgery, The First Affiliated Hospital of the University of Science and Technology of China, China.
Department of General Surgery, Anhui Provincial Hospital Affiliated to the Anhui Medical University of China, China.
Stem Cells Int. 2020 Apr 17;2020:2803747. doi: 10.1155/2020/2803747. eCollection 2020.
Adipose-derived mesenchymal stem cells (ADMSCs) have been used for treating tissue injury, and preactivation enhances their therapeutic effect. This study is aimed at investigating the therapeutic effect of activated ADMSCs by IL-1 on the intestinal ischaemia-reperfusion (IR) injury and exploring potential mechanisms. ADMSCs were pretreated with IL-1 in vitro, and activation of ADMSCs was assessed by -SMA and COX-2 expressions and secretary function. Activated ADMSCs was transplanted into IR-injured intestine in a mouse model, and therapeutic effect was evaluated. In addition, to explore underlying mechanisms, COX-2 expression was silenced to investigate its role in activated ADMSCs for treatment of intestinal IR injury. When ADMSCs were pretreated with 50 ng/ml IL-1 for 24 hr, expressions of -SMA and COX-2 were significantly upregulated, and secretions of PGE, SDF-1, and VEGF were increased. When COX-2 was silenced, the effect of IL-1 treatment was abolished. Activated ADMSCs with IL-1 significantly suppressed inflammation and apoptosis and enhanced healing of intestinal IR injury in mice, and these effects were impaired by COX-2 silencing. The results of RNA sequencing suggested that compared with the IR injury group activated ADMSCs induced alterations in mRNA expression and suppressed the activation of the NF-B-P65, MAPK-ERK1/2, and PI3K-AKT pathways induced by intestinal IR injury, whereas silencing COX-2 impaired the suppressive effect of activated ADMSCs on these pathway activations induced by IR injury. These data suggested that IL-1 pretreatment enhanced the therapeutic effect of ADMSCs on intestinal IR injury repairing via activating ADMSC COX-2-PGE signaling axis and via suppressing the NF-B-P65, MAPK-ERK1/2, and PI3K-AKT pathways in the intestinal IR-injured tissue.
脂肪来源的间充质干细胞（ADMSCs）已被用于治疗组织损伤，预激活可增强其治疗效果。本研究旨在探讨白细胞介素-1（IL-1）激活的ADMSCs对肠道缺血再灌注（IR）损伤的治疗作用，并探索其潜在机制。在体外用IL-1预处理ADMSCs，并通过α-平滑肌肌动蛋白（α-SMA）和环氧化酶-2（COX-2）的表达及分泌功能评估ADMSCs的激活情况。将激活的ADMSCs移植到小鼠IR损伤肠道模型中，并评估治疗效果。此外，为探索潜在机制，使COX-2表达沉默以研究其在激活的ADMSCs治疗肠道IR损伤中的作用。当ADMSCs用50 ng/ml IL-1预处理24小时时，α-SMA和COX-2的表达显著上调，前列腺素E（PGE）、基质细胞衍生因子-1（SDF-1）和血管内皮生长因子（VEGF）的分泌增加。当COX-2沉默时，IL-1治疗的效果被消除。IL-1激活的ADMSCs显著抑制小鼠肠道IR损伤的炎症和凋亡，并促进愈合，而COX-2沉默会削弱这些作用。RNA测序结果表明，与IR损伤组相比，激活的ADMSCs诱导mRNA表达改变，并抑制肠道IR损伤诱导的核因子κB-P65（NF-κB-P65）、丝裂原活化蛋白激酶-细胞外信号调节激酶1/2（MAPK-ERK1/2）和磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-AKT）信号通路的激活，而沉默COX-2会削弱激活的ADMSCs对IR损伤诱导的这些信号通路激活的抑制作用。这些数据表明，IL-1预处理通过激活ADMSC的COX-2-PGE信号轴以及抑制肠道IR损伤组织中的NF-κB-P65, MAPK-ERK1/2和PI3K-AKT信号通路，增强了ADMSCs对肠道IR损伤修复的治疗效果。
