rBMSCs/ITGA5B1通过增强一氧化氮生成促进人血管平滑肌细胞分化。
rBMSCs/ITGA5B1 Promotes Human Vascular Smooth Muscle Cell Differentiation via Enhancing Nitric Oxide Production.
作者信息
Zhang Yingxin, Ding Jie, Xu Cong, Yang Hongli, Xia Peng, Ma Shengjun, Chen Haiying
机构信息
Central Laboratory of Liaocheng People's Hospital, Liaocheng, Shandong, China.
Department of Cardiology, Liaocheng People's Hospital, Liaocheng, Shandong, China.
出版信息
Int J Stem Cells. 2018 Nov 30;11(2):168-176. doi: 10.15283/ijsc18079.
BACKGROUND AND OBJECTIVES
Previous studies have shown that integrins alpha5beta1 (ITGA5B1) gene-modified rat bone marrow mesenchymal stem cells (rBMSCs) could prevent cell anoikis and increase the nitric oxide (NO) production. Here we examined the capability of rBMSCs/ITGA5B1 on the phenotype modulation of Human Pulmonary Artery Smooth Muscle Cell (HPASMC)
METHODS AND RESULTS
The synthetic (dedifferentiated) phenotype of HPASMC was induced by monocrotaline (MCT, 1M) for 24 h and then co-cultured with rBMSCs/ITGA5B1 in a transwell culture system. The activation of NO/cGMP (nitric oxide/Guanosine-3', 5'-cyclic monophosphate) signaling was investigated in HPASMC. The changes of pro-inflammatory factors, oxidative stress, vasodilator, vasoconstrictor, contractile and synthetic genes, and the morphological changes of HPASMC were investigated. The results of this study showed that the NO/cGMP signal, endothelial nitric oxide synthase (eNOS) expression, the expression of the vasoprotective genes heme oxygenase-1 (HMOX1) and prostaglandin-endoperoxide synthase 2 (PTGS2) were increased, but the expression of transforming growth factor-1 (TGF-1), CCAAT/enhancer-binding proteins delta (Cebpd), Krüppel-like factor 4 (KLF4), and activating transcription factor 4 (ATF4) were reduced in MCT treated HPASMC co-cultured with rBMSCs/ITGA5B1. The synthetic smooth muscle cells (SMCs) phenotype markers thrombospondin-1, epiregulin and the vasoconstrictor endothelin (ET)-1, thromboxane A2 receptor (TbxA2R) were down-regulated, whereas the contractile SMCs phenotype marker transgelin expression was up-regulated by rBMSCs/ITGA5B1. Furthermore, rBMSCs/ITGA5B1 promoted the morphological restoration from synthetic (dedifferentiation) to contractile (differentiation) phenotype in MCT treated HPASMC.
CONCLUSIONS
rBMSCs/ITGA5B1 could inhibit inflammation and oxidative stress related genes to promote the HPASMC cell differentiation by activation NO/cGMP signal.
背景与目的
既往研究表明，整合素α5β1（ITGA5B1）基因修饰的大鼠骨髓间充质干细胞（rBMSCs）可防止细胞失巢凋亡并增加一氧化氮（NO）生成。在此，我们检测了rBMSCs/ITGA5B1对人肺动脉平滑肌细胞（HPASMC）表型调节的能力。
方法与结果
用野百合碱（MCT，1M）诱导HPASMC的合成（去分化）表型24小时，然后在Transwell培养系统中与rBMSCs/ITGA5B1共培养。研究了HPASMC中NO/cGMP（一氧化氮/鸟苷-3'，5'-环磷酸）信号的激活情况。研究了促炎因子、氧化应激、血管舒张剂、血管收缩剂、收缩和合成基因的变化以及HPASMC的形态变化。本研究结果表明，在与rBMSCs/ITGA5B1共培养的MCT处理的HPASMC中，NO/cGMP信号、内皮型一氧化氮合酶（eNOS）表达、血管保护基因血红素加氧酶-1（HMOX1）和前列腺素内过氧化物合酶2（PTGS2）的表达增加，但转化生长因子-1（TGF-1）、CCAAT/增强子结合蛋白δ（Cebpd）、Krüppel样因子4（KLF4）和激活转录因子4（ATF4）的表达降低。rBMSCs/ITGA5B1下调了合成型平滑肌细胞（SMCs）表型标志物血小板反应蛋白-1、表皮调节素和血管收缩剂内皮素（ET）-1、血栓素A2受体（TbxA2R），而上调了收缩型SMCs表型标志物原肌球蛋白的表达。此外，rBMSCs/ITGA5B1促进了MCT处理的HPASMC从合成（去分化）表型到收缩（分化）表型的形态恢复。
结论
rBMSCs/ITGA5B1可通过激活NO/cGMP信号抑制炎症和氧化应激相关基因，促进HPASMC细胞分化。
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