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Hypoxia-Preconditioned Wharton’s Jelly-Derived Mesenchymal Stem Cells Mitigate Stress-Induced Apoptosis and Ameliorate Human Islet Survival and Function in Direct Contact Coculture System
Stem Cells International ( IF 4.3 ) Pub Date : 2020-12-17 , DOI: 10.1155/2020/8857457
Somayeh Keshtkar 1, 2, 3 , Maryam Kaviani 2 , Zahra Jabbarpour 1 , Fatemeh Sabet Sarvestani 2 , Mohammad Hossein Ghahremani 1 , Elaheh Esfandiari 2 , Mahdokht Hossein Aghdaei 2 , Saman Nikeghbalian 4 , Alireza Shamsaeefar 4 , Bita Geramizadeh 2 , Negar Azarpira 2, 3
Affiliation  

Protection of isolated pancreatic islets against hypoxic and oxidative damage-induced apoptosis is essential during a pretransplantation culture period. A beneficial approach to maintain viable and functional islets is the coculture period with mesenchymal stem cells (MSCs). Hypoxia preconditioning of MSCs (Hpc-MSCs) for a short time stimulates the expression and secretion of antiapoptotic, antioxidant, and prosurvival factors. The aim of the present study was to evaluate the survival and function of human islets cocultured with Hpc-MSCs. Wharton’s jelly-derived MSCs were subjected to hypoxia (5% O2: Hpc) or normoxia (20% O2: Nc) for 24 hours and then cocultured with isolated human islets in direct and indirect systems. Assays of viability and apoptosis, along with the production of reactive oxygen species (ROS), hypoxia-inducible factor 1-alpha (HIF-1α), apoptotic pathway markers, and vascular endothelial growth factor (VEGF) in the islets, were performed. Insulin and C-peptide secretions as islet function were also evaluated. Hpc-MSCs and Nc-MSCs significantly reduced the ROS production and HIF-1α protein aggregation, as well as downregulation of proapoptotic proteins and upregulation of antiapoptotic marker along with increment of VEGF secretion in the cocultured islet. However, the Hpc-MSCs groups were better than Nc-MSCs cocultured islets. Hpc-MSCs in both direct and indirect coculture systems improved the islet survival, while promotion of function was only significant in the direct cocultured cells. Hpc potentiated the cytoprotective and insulinotropic effects of MSCs on human islets through reducing stressful markers, inhibiting apoptosis pathway, enhancing prosurvival factors, and promoting insulin secretion, especially in direct coculture system, suggesting the effective strategy to ameliorate the islet quality for better transplantation outcomes.

中文翻译:

缺氧预处理的沃顿氏胶源性间充质干细胞可减轻应激诱导的细胞凋亡,改善人胰岛的存活和直接接触共培养系统的功能

在移植前的培养期间,保护胰岛免受低氧和氧化损伤诱导的细胞凋亡至关重要。维持生存和功能性胰岛的一种有益方法是与间充质干细胞(MSC)共培养。MSCs(Hpc-MSCs)的缺氧预处理可在短时间内刺激抗凋亡,抗氧化剂和生存因子的表达和分泌。本研究的目的是评估与Hpc-MSC共培养的人类胰岛的存活和功能。沃顿氏胶冻来源的MSC处于低氧(5%O 2:Hpc)或常氧(20%O 2:Nc)24小时,然后在直接和间接系统中与孤立的人类胰岛共培养。进行了活力和细胞凋亡的测定,以及胰岛中活性氧物质(ROS),缺氧诱导因子1-α(HIF- ),凋亡途径标记和血管内皮生长因子(VEGF)的产生。还评估了胰岛功能的胰岛素和C肽分泌。Hpc-MSC和Nc-MSC显着降低ROS的产生和HIF- 共聚集的胰岛中,蛋白聚集,凋亡蛋白的下调和抗凋亡标记的上调以及VEGF分泌的增加。但是,Hpc-MSCs组优于Nc-MSCs共培养的胰岛。直接和间接共培养系统中的Hpc-MSC均改善了胰岛的存活,而功能的提升仅在直接共培养细胞中才有意义。Hpc通过减少应激标志物,抑制细胞凋亡途径,增强存活因子和促进胰岛素分泌来增强MSC对人胰岛的细胞保护和促胰岛素作用,特别是在直接共培养系统中,这是改善胰岛质量以改善移植结果的有效策略。
更新日期:2020-12-17
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