Sharifkhodaei Zohreh, Liu Cambrian Y, Girish Nandini, Huang Ying, Punit Shivesh, Washington M Kay, Polk D Brent
Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
Department of Medicine, The University of Chicago, Chicago, IL, USA.
iScience. 2023 Sep 4;26(10):107829. doi: 10.1016/j.isci.2023.107829. eCollection 2023 Oct 20.
Colonic epithelial repair is a key determinant of health. Repair involves changes in epithelial differentiation, an extensive proliferative response, and upregulation of regeneration-associated "fetal-like" transcripts, including (Sca-1), that represent Yap1 and interferon targets. However, little is known about how this regenerative program terminates and how homeostasis is restored during injury and inflammation. Here we show that, after the initial entry into the regenerative state, the subsequent upregulation of tumor necrosis factor (TNF) receptor 2 (R2, TNFR2, ) clears the regenerative signaling and restores homeostatic patterns of epithelial differentiation. Targeted deletion of epithelial TNFR2 and in colonoid cultures revealed persistent expression of , hyperproliferation, and reduced secretory differentiation. Moreover, mice lacking epithelial TNFR2 also failed to complete colon ulcer healing, suggesting that partial resolution of regenerative signaling is essential for the completion of the repair process. These results demonstrate how epithelial cells dynamically leverage a colitis-associated cytokine to choreograph repair.
结肠上皮修复是健康的关键决定因素。修复涉及上皮分化的变化、广泛的增殖反应以及与再生相关的“胎儿样”转录本的上调，包括代表Yap1和干扰素靶点的（Sca-1）。然而，对于这种再生程序如何终止以及在损伤和炎症期间如何恢复内环境稳态知之甚少。在这里，我们表明，在最初进入再生状态后，肿瘤坏死因子（TNF）受体2（R2，TNFR2， ）的随后上调清除了再生信号并恢复了上皮分化的稳态模式。在结肠样培养物中靶向缺失上皮TNFR2 显示 持续表达、过度增殖和分泌分化减少。此外，缺乏上皮TNFR2的小鼠也未能完成结肠溃疡愈合，这表明再生信号的部分消退对于修复过程的完成至关重要。这些结果证明了上皮细胞如何动态利用与结肠炎相关的细胞因子来编排修复过程。
