PDF(Pubmed)
Abstract：
Pancreatic islet transplantation is proposed as a cure for type 1 diabetes mellitus (T1D). Despite its success in optimal regulation of glucose levels, limitations in longevity of islet grafts still require innovative solutions. Inflammatory stress post-transplantation and loss of extracellular matrix attribute to the limited β-cell survival. Pancreatic stellate cells (PSCs), identified as pancreatic-specific stromal cells, have the potential to play a crucial role in preserving islet survival. Our study aimed to determine the effects of PSCs co-cultured with human CM β-cells and human islets under inflammatory stress induced by a cytokine cocktail of IFN-γ, TNF-α and IL-1β. Transwell culture inserts were utilized to assess the paracrine impact of PSCs on β-cells, alongside co-cultures enabling direct interaction between PSCs and human islets. We found that co-culturing PSCs with human CM β-cells and human cadaveric islets had rescuing effects on cytokine-induced stress. Effects were different under normoglycemic and hyperglycemic conditions. PSCs were associated with upregulation of β-cell mitochondrial activity and suppression of inflammatory gene expression. The rescuing effects exist both in indirect and direct co-culture methods. Furthermore, we tested whether PSCs have rescuing effects on human islets in conventional alginate-based microcapsules and in composite microcapsules composed of alginate-pectin collagen type IV, laminin sequence RGD, Nec-1, and amino acid. PSCs partially prevented cytokine-induced stress in both systems, but beneficial effects were stronger in composite capsules. Our findings show novel effects of PSCs on islet health. Islets and PSCs coculturing or co-transplantation might mitigate the inflammation stress and improve islet transplantation outcomes.
摘要：
建议将胰岛移植作为1型糖尿病（T1D）的治疗方法。尽管它在优化调节葡萄糖水平方面取得了成功，胰岛移植物寿命的限制仍然需要创新的解决方案。移植后的炎性应激和细胞外基质的损失归因于有限的β细胞存活。胰腺星状细胞(PSC),鉴定为胰腺特异性基质细胞，有可能在保护胰岛生存方面发挥关键作用。我们的研究旨在确定在IFN-γ细胞因子混合物诱导的炎症应激下，与人CMβ细胞和人胰岛共培养的PSC的作用。TNF-α和IL-1β。Transwell培养插入物用于评估PSC对β细胞的旁分泌影响，与共同培养一起，使PSC和人类胰岛之间能够直接相互作用。我们发现，将PSC与人CMβ细胞和人尸体胰岛共培养对细胞因子诱导的应激具有挽救作用。在正常血糖和高血糖条件下效果不同。PSC与β细胞线粒体活性的上调和炎症基因表达的抑制有关。在间接和直接共培养方法中都存在挽救作用。此外，我们测试了PSC是否在常规的基于藻酸盐的微胶囊和由藻酸盐-果胶胶原蛋白IV型组成的复合微胶囊中对人类胰岛有挽救作用，层粘连蛋白序列RGD,Nec-1和氨基酸。PSC在两个系统中部分预防细胞因子诱导的应激，但是复合胶囊的有益效果更强。我们的发现显示了PSC对胰岛健康的新作用。胰岛和PSC共培养或共移植可能减轻炎症应激并改善胰岛移植结果。
