Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Nat Commun. 2023 Sep 5;14(1):5411. doi: 10.1038/s41467-023-40993-5.
Intestinal stem cells (ISCs) maintain the epithelial lining of the intestines, but mechanisms regulating ISCs and their niche after damage remain poorly understood. Utilizing radiation injury to model intestinal pathology, we report here that the Interleukin-33 (IL-33)/ST2 axis, an immunomodulatory pathway monitored clinically as an intestinal injury biomarker, regulates intrinsic epithelial regeneration by inducing production of epidermal growth factor (EGF). Three-dimensional imaging and lineage-specific RiboTag induction within the stem cell compartment indicated that ISCs expressed IL-33 in response to radiation injury. Neighboring Paneth cells responded to IL-33 by augmenting production of EGF, which promoted ISC recovery and epithelial regeneration. These findings reveal an unknown pathway of niche regulation and crypt regeneration whereby the niche responds dynamically upon injury and the stem cells orchestrate regeneration by regulating their niche. This regenerative circuit also highlights the breadth of IL-33 activity beyond immunomodulation and the therapeutic potential of EGF administration for treatment of intestinal injury.
肠干细胞（ISCs）维持肠道的上皮衬里，但调节 ISCs 及其龛位的机制在损伤后仍知之甚少。本研究利用辐射损伤来模拟肠道病理学，报告了白细胞介素 33（IL-33）/ST2 轴作为一种临床监测的肠道损伤生物标志物，通过诱导表皮生长因子（EGF）的产生来调节固有上皮再生。三维成像和干细胞龛位中的谱系特异性 RiboTag 诱导表明，ISCs 在辐射损伤后表达 IL-33。相邻的 Paneth 细胞通过增加 EGF 的产生来响应 IL-33，从而促进 ISC 恢复和上皮再生。这些发现揭示了一种未知的龛位调节和隐窝再生途径，其中龛位在损伤后会动态响应，而干细胞通过调节其龛位来协调再生。这个再生回路还突出了 IL-33 活性超越免疫调节的广泛性，以及 EGF 给药治疗肠道损伤的治疗潜力。
