Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany.
Unit for Mycotic and Parasitic Agents and Mycobacteria, Robert Koch-Institute (RKI), 13353 Berlin, Germany.
Development. 2021 Nov 1;148(21). doi: 10.1242/dev.199683. Epub 2021 Nov 9.
Although the role of the transcription factor NF-κB in intestinal inflammation and tumor formation has been investigated extensively, a physiological function of NF-κB in sustaining intestinal epithelial homeostasis beyond inflammation has not been demonstrated. Using NF-κB reporter mice, we detected strong NF-κB activity in Paneth cells, in '+4/+5' secretory progenitors and in scattered Lgr5+ crypt base columnar stem cells of small intestinal (SI) crypts. To examine NF-κB functions in SI epithelial self-renewal, mice or SI crypt organoids ('mini-guts') with ubiquitously suppressed NF-κB activity were used. We show that NF-κB activity is dispensable for maintaining SI epithelial proliferation, but is essential for ex vivo organoid growth. Furthermore, we demonstrate a dramatic reduction of Paneth cells in the absence of NF-κB activity, concomitant with a significant increase in goblet cells and immature intermediate cells. This indicates that NF-κB is required for proper Paneth versus goblet cell differentiation and for SI epithelial homeostasis, which occurs via regulation of Wnt signaling and Sox9 expression downstream of NF-κB. The current study thus presents evidence for an important role for NF-κB in intestinal epithelial self-renewal.
尽管转录因子 NF-κB 在肠道炎症和肿瘤形成中的作用已经被广泛研究，但 NF-κB 在维持肠道上皮细胞稳态方面的生理功能超出炎症范围尚未得到证实。使用 NF-κB 报告基因小鼠，我们在潘氏细胞、‘+4/+5’分泌祖细胞和小肠（SI）隐窝中散在的 Lgr5+隐窝基底柱状干细胞中检测到强烈的 NF-κB 活性。为了研究 NF-κB 在 SI 上皮细胞自我更新中的功能，我们使用了 NF-κB 活性普遍受到抑制的小鼠或 SI 隐窝类器官（“迷你肠道”）。我们表明，NF-κB 活性对于维持 SI 上皮细胞增殖不是必需的，但对于体外类器官的生长是必需的。此外，我们发现在缺乏 NF-κB 活性的情况下，潘氏细胞明显减少，同时杯状细胞和不成熟的中间细胞显著增加。这表明 NF-κB 对于潘氏细胞与杯状细胞的分化以及 SI 上皮细胞的稳态是必需的，这种稳态是通过 NF-κB 下游的 Wnt 信号和 Sox9 表达的调节来实现的。因此，本研究为 NF-κB 在肠道上皮细胞自我更新中的重要作用提供了证据。
