Xie Juncong, Liu Bolong, Chen Jialiang, Xu Yuancheng, Zhan Hailun, Yang Fei, Li Wenbiao, Zhou Xiangfu
Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Biochem Biophys Res Commun. 2018 Jan 1;495(1):546-552. doi: 10.1016/j.bbrc.2017.11.072. Epub 2017 Nov 11.
Interstitial cystitis (IC) is a bladder syndrome characterized by pelvic pain and urinary frequency without infection or other identifiable pathology. There are no effective treatments to cure IC. This study investigated the effects of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) injection on IC rat model. Furthermore, we used a coculture system to find the possible molecular mechanism on the human uroepithelial cells (SV-HUC-1), which was the cell model of IC. A rat model of IC was established via systemic injection with cyclophosphamide (CYP) and a cell model of IC was induced by being exposed to tumor necrosis factor (TNF)-α (10 ng/ml). After one week, UC-MSCs injection significantly ameliorated the bladder voiding function in IC rat model. And the Histo- and immunohistochemical analyses showed that UC-MSCs can repair impaired bladder, reduce mast cell infiltration and inhibit apoptosis of urothelium. ELISA results showed that UC-MSCs can decrease IL-1β, IL-6 and TNF-α in bladder. In the coculture system, UC-MSCs can promote proliferation of impaired SV-HUC-1 cells, and inhibit apoptosis. However, while knocked down EGF secreted by UC-MSCs with siRNA, the effects would be weaken. Western blot showed that UC-MSCs increase protein expression levels of p-AKT and p-mTOR in SV-HUC-1 cells, and decrease the levels of cleaved caspase-3. Taken together, we provide evidence that UC-MSCs therapy can successfully alleviate IC in a preclinical animal Model and cell model by alleviating inflammation, promoting proliferation and inhibiting apoptosis. In addition, we demonstrate that the AKT/mTOR signaling pathway was activated.
间质性膀胱炎（IC）是一种膀胱综合征，其特征为盆腔疼痛和尿频，且无感染或其他可识别的病理状况。目前尚无治愈IC的有效疗法。本研究调查了人脐带间充质干细胞（UC-MSCs）注射对IC大鼠模型的影响。此外，我们使用共培养系统来寻找IC细胞模型——人尿路上皮细胞（SV-HUC-1）中可能的分子机制。通过全身注射环磷酰胺（CYP）建立IC大鼠模型，并通过暴露于肿瘤坏死因子（TNF）-α（10 ng/ml）诱导IC细胞模型。一周后，UC-MSCs注射显著改善了IC大鼠模型的膀胱排尿功能。组织学和免疫组化分析表明，UC-MSCs可修复受损膀胱，减少肥大细胞浸润并抑制尿路上皮细胞凋亡。酶联免疫吸附测定（ELISA）结果显示，UC-MSCs可降低膀胱中白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和TNF-α的水平。在共培养系统中，UC-MSCs可促进受损SV-HUC-1细胞的增殖并抑制其凋亡。然而，当用小干扰RNA（siRNA）敲低UC-MSCs分泌的表皮生长因子（EGF）时，这些作用会减弱。蛋白质免疫印迹法（Western blot）显示，UC-MSCs可增加SV-HUC-1细胞中磷酸化蛋白激酶B（p-AKT）和磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）的表达水平，并降低裂解的半胱天冬酶-3（cleaved caspase-3）的水平。综上所述，我们提供的证据表明，在临床前动物模型和细胞模型中，UC-MSCs疗法可通过减轻炎症、促进增殖和抑制凋亡成功缓解IC。此外，我们证明了AKT/mTOR信号通路被激活。
