https://ror.org/04rq5mt64 Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
https://ror.org/04rq5mt64 Institute for Genome Science, University of Maryland School of Medicine, Baltimore, MD, USA.
Life Sci Alliance. 2023 Sep 11;6(11). doi: 10.26508/lsa.202302152. Print 2023 Nov.
Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to the mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.
肠道上皮的快速自我更新需要肠道干细胞（ISCs）的活性，这些干细胞与隐窝底部的潘氏细胞（PCs）混合在一起。PCs 提供多种分泌和表面结合的生态位信号，并在调节 ISC 增殖方面发挥重要作用。在这里，我们表明，通过线粒体的 RNA 结合蛋白 HuR 对 PC 功能的控制会通过改变 ISC 活性来影响肠道黏膜的生长。在小鼠中靶向敲除 HuR 会破坏 PC 的基因表达谱，减少 PC 衍生的生态位因子，并损害 ISC 功能，导致肠道上皮的更新受到抑制。来自患有严重手术障碍的患者的人肠道黏膜显示出组织 HuR 和 PC/ISC 生态位功能障碍的水平降低，同时伴有黏膜生长紊乱。HuR 缺失通过降低几种线粒体相关蛋白（包括肠上皮细胞中的 PHB1）的水平导致线粒体损伤，而 HuR 通过防止 microRNA-195 结合到 mRNA 上来增强 PHB1 的表达。这些结果表明 HuR 对于维持 PC/ISC 生态位的完整性是必不可少的，并强调了 PC/ISC 生态位缺陷在肠道黏膜萎缩发病机制中的新作用。
