Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases affecting premature infants. It has been shown that NEC is associated with disrupted intestinal barrier and dysregulated endoplasmic reticulum (ER)‐stress response. It has also been shown that stem cells derived from amniotic fluid (AFSC) rescued intestinal injury in experimental NEC. Herein, we hypothesized that the beneficial effects of AFSC in the injured intestine are due to the restoration of intestinal barrier function. We evaluated intestinal barrier function using an ex vivo intestinal organoid model of NEC. We found that AFSC restored the expression and localization of tight junction proteins in intestinal organoids, and subsequently decreased epithelial permeability. AFSC rescued tight junction expression by inducing a protective ER stress response that prevents epithelial cell apoptosis in injured intestinal organoids. Finally, we validated these results in our experimental mouse model of NEC and confirmed that AFSC induced sustained ER stress and prevented intestinal apoptosis. This response led to the restoration of tight junction expression and localization, which subsequently reduced intestinal permeability in NEC pups. These findings confirm that intestinal barrier function is disrupted during NEC intestinal injury, and further demonstrate the disruption can be reversed by the administration of AFSC through the activation of the ER stress pathway. This study provides insight into the pathogenesis of NEC and highlights potential therapeutic targets for the treatment of NEC.

中文翻译：

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羊水干细胞在坏死性小肠结肠炎期间可通过调节内质网应激来挽救肠上皮紧密连接和通透性

坏死性小肠结肠炎 (NEC) 是影响早产儿的最严重的胃肠道疾病之一。已经表明 NEC 与肠道屏障破坏和内质网 (ER) 应激反应失调有关。还表明，来自羊水 (AFSC) 的干细胞在实验性 NEC 中挽救了肠道损伤。在此，我们假设 AFSC 在受损肠道中的有益作用是由于肠道屏障功能的恢复。我们使用 NEC 的离体肠道类器官模型评估了肠道屏障功能。我们发现 AFSC 恢复了肠道类器官中紧密连接蛋白的表达和定位，随后降低了上皮通透性。AFSC 通过诱导保护性内质网应激反应来防止受损肠道类器官中的上皮细胞凋亡，从而挽救了紧密连接的表达。最后，我们在我们的 NEC 实验小鼠模型中验证了这些结果，并证实 AFSC 诱导持续的 ER 应激并阻止肠道细胞凋亡。这种反应导致紧密连接表达和定位的恢复，从而降低了 NEC 幼崽的肠道通透性。这些发现证实了在 NEC 肠道损伤期间肠道屏障功能被破坏，并进一步证明可以通过激活 ER 应激途径，通过施用 AFSC 来逆转这种破坏。这项研究提供了对 NEC 发病机制的深入了解，并突出了 NEC 治疗的潜在治疗靶点。