Glutamine Regulates Gene Expression Profiles to Increase the Proliferation of Porcine Intestinal Epithelial Cells and the Expansion of Intestinal Stem Cells.
Glutamine Regulates Gene Expression Profiles to Increase the Proliferation of Porcine Intestinal Epithelial Cells and the Expansion of Intestinal Stem Cells.
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DOI：
10.3390/ani13182917
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发表时间：
2023-09-14
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肠上皮细胞是身体中更新最快的组织之一。这一过程由肠干细胞驱动，并受到三磷酸腺苷供应的极大影响。谷氨酰胺是肠上皮细胞的首选能量底物，不像身体中的大多数组织更喜欢葡萄糖。然而，需要更多地了解谷氨酰胺如何影响肠上皮细胞中的基因表达。为了解决这一问题，本研究旨在通过探索基因表达谱来确定谷氨酰胺诱导肠上皮细胞生长的必需基因和信号。结果表明，谷氨酰胺可能上调脱氧核糖核酸复制许可因子，增加增殖相关信号通路，抑制炎症相关通路。因此，这种机制导致肠上皮细胞的增殖和肠干细胞的扩增。了解这些关键的目标提供了新的见解调节肠上皮细胞的稳态，特别是在猪生产。肠上皮以其快速自我更新而闻名，谷氨酰胺在为生物合成提供碳和氮方面至关重要。然而，了解谷氨酰胺如何影响肠上皮细胞中的基因表达是有限的，并且确定参与调节肠上皮细胞生长的必需基因和信号尤其具有挑战性。在这项研究中，谷氨酰胺补充剂表现出强劲的加速肠上皮细胞增殖和干细胞扩增。RNA测序表明对照组和谷氨酰胺补充组之间存在不同的转录组变化，确定了925个上调和1152个下调基因。上调的DEG富集在细胞周期的KEGG通路和DNA复制起始、磷脂酰肌醇3-激酶活性调节、DNA复制、微染色体维持蛋白（MCM）复合物和ATP结合的GO术语中，而下调的DEG富集在p53信号通路、TNF信号通路、以及JAK-STAT信号通路和GO术语的炎症反应和内质网应激应答的内在凋亡信号通路。此外，GSEA分析揭示了细胞周期，DNA复制起始，ATP依赖性RNA解旋酶活性的显著上调，以及TNF信号通路的下调。交叉基因的蛋白质-蛋白质关联网络突出了DNA复制许可因子（MCM 3、MCM 6和MCM 10）在促进肠上皮细胞响应谷氨酰胺的生长中的重要性。基于这些发现，我们提出谷氨酰胺可能上调DNA复制许可因子，导致PI 3 K/Akt信号传导增加和TNF、JAK-STAT和p53通路的抑制。因此，这一机制导致猪小肠上皮细胞的增殖和肠干细胞的扩增。
The intestinal epithelium is one of the tissues that renews the fastest in the body. This process is driven by intestinal stem cells and is greatly influenced by adenosine triphosphate supply. Glutamine is the preferred energy substrate for the intestinal epithelium, unlike most tissues in the body that prefer glucose. However, there needs to be more understanding of how glutamine affects gene expression in the intestinal epithelium. To address this gap, this study aimed to identify the essential genes and signals involved in glutamine-induced growth of intestinal epithelial cells by exploring gene expression profiles. The results showed that glutamine might upregulate deoxyribonucleic acid replication licensing factors, increasing proliferation-related signaling and suppressing inflammation-related pathways. Consequently, this mechanism leads to the proliferation of intestinal epithelial cells and the expansion of intestinal stem cells. Understanding these crucial targets provides new insight into regulating the homeostasis of the intestinal epithelium, particularly in porcine production. The intestinal epithelium is known for its rapid self-renewal, and glutamine is crucial in providing carbon and nitrogen for biosynthesis. However, understanding how glutamine affects gene expression in the intestinal epithelium is limited, and identifying the essential genes and signals involved in regulating intestinal epithelial cell growth is particularly challenging. In this study, glutamine supplementation exhibited a robust acceleration of intestinal epithelial cell proliferation and stem cell expansion. RNA sequencing indicated diverse transcriptome changes between the control and glutamine supplementation groups, identifying 925 up-regulated and 1152 down-regulated genes. The up-regulated DEGs were enriched in the KEGG pathway of cell cycle and GO terms of DNA replication initiation, regulation of phosphatidylinositol 3-kinase activity, DNA replication, minichromosome maintenance protein (MCM) complex, and ATP binding, whereas the down-regulated DEGs were enriched in the KEGG pathway of p53 signaling pathway, TNF signaling pathway, and JAK-STAT signaling pathway and GO terms of inflammatory response and intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress. Furthermore, GSEA analysis revealed a significant up-regulation of the cell cycle, DNA replication initiation, ATP-dependent RNA helicase activity, and down-regulation of the TNF signaling pathway. The protein–protein association network of the intersecting genes highlighted the significance of DNA replication licensing factors (MCM3, MCM6, and MCM10) in promoting intestinal epithelial growth in response to glutamine. Based on these findings, we propose that glutamine may upregulate DNA replication licensing factors, leading to increased PI3K/Akt signaling and the suppression of TNF, JAK-STAT, and p53 pathways. Consequently, this mechanism results in the proliferation of porcine intestinal epithelial cells and the expansion of intestinal stem cells.
影响因子：
4.5
作者：
Schulze Holthausen J;Schregel J;Sciascia QL;Li Z;Tuchscherer A;Vahjen W;Metges CC;Zentek J
通讯作者：
Zentek J