肠内分泌细胞调节肠道屏障的通透性

IF 5 2区 生物学 Q2 CELL BIOLOGY
Jennifer G Nwako, Sparsh D Patel, Taevon J Roach, Saanvi R Gupte, Samara G Williams, Anne Marie Riedman, Heather A McCauley
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引用次数: 0

摘要

肠上皮屏障对营养吸收和防止摄入病原体和外来物质至关重要。屏障的完整性是通过对炎症信号敏感的紧密连接来维持的,从而形成一个前馈循环,其渗透性越来越强,进一步驱动炎症,是炎症性肠病的标志。目前还没有改善肠上皮屏障的治疗策略。我们假设肠内分泌细胞可能在维持屏障完整性方面发挥了未被认识到的作用。为了验证这一假设,我们在Transwell过滤器上植入了肠内分泌细胞遗传缺失的人肠道样肠,并评估了经上皮电阻、细胞旁通透性以及连接蛋白的定位和丰度。我们发现肠内分泌细胞需要在隐窝样“茎”和绒毛样分化培养中维持健康的屏障。此外,外源性补充肠内分泌缺陷培养物的激素肽酪氨酸酪氨酸(PYY)和生长抑素类似物奥替肽足以在基线和炎症细胞因子肿瘤坏死因子(TNF)存在时挽救这种屏障缺陷的许多方面。令人惊讶的是,这些屏障功能的改善在很大程度上独立于连接蛋白occludens 1、occludin和claudin-2蛋白丰度的变化。这些发现支持肠内分泌细胞在炎症刺激下增强上皮屏障功能的新作用,并为开发改善肠道屏障的疗法提供了机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enteroendocrine Cells Regulate Intestinal Barrier Permeability.

The intestinal epithelial barrier is essential for nutrient absorption and protection against ingested pathogens and foreign substances. Barrier integrity is maintained by tight junctions which are sensitive to inflammatory signals, thus creating a feed-forward loop with an increasingly permeable barrier that further drives inflammation and is the hallmark of inflammatory bowel disease. There are currently no therapeutic strategies to improve the intestinal epithelial barrier. We hypothesized that enteroendocrine cells may play an unappreciated role in maintaining barrier integrity. To test this hypothesis, we seeded human intestinal enteroids with genetic loss of enteroendocrine cells on Transwell filters and evaluated transepithelial electrical resistance, paracellular permeability, and the localization and abundance of junctional proteins. We found that enteroendocrine cells were required to maintain a healthy barrier in crypt-like "stem" and villus-like differentiated cultures. Additionally, exogenous supplementation of enteroendocrine-deficient cultures with the hormones peptide tyrosine tyrosine (PYY) and the somatostatin analog octreotide was sufficient to rescue many aspects of this barrier defect both at baseline and in the presence of the inflammatory cytokine tumor necrosis factor (TNF). Surprisingly, these improvements in barrier function occurred largely independently of changes in protein abundance of junctional proteins zona-occludens 1, occludin, and claudin-2. These findings support a novel role for enteroendocrine cells in augmenting epithelial barrier function in the presence of inflammatory stimuli and present an opportunity for developing therapies to improve the intestinal barrier.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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