Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth.
Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth.
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DOI：
10.1242/dmm.049692
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发表时间：
2023-04-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
由基质成纤维细胞分泌的生长因子调节肠上皮。基质源性表皮生长因子（EGF）家族配体与上皮再生和肿瘤发生有关，但其具体作用和相关机制尚不清楚。在这里，我们使用初级肠类器官建模稳态，损伤和致瘤上皮细胞来评估成纤维细胞衍生的EGF家族配体神经调节蛋白1（NRG 1）和上皮调节蛋白（EREG）如何调节肠上皮。NRG 1仅在基质中表达，强烈增加隐窝出芽并保护肠上皮类器官免受辐射诱导的损伤。NRG 1还诱导上皮细胞的再生特征，包括胎儿样转录组、Lgr 5+干细胞池的抑制和上皮肌动蛋白细胞骨架的重塑。有趣的是，与EGF和EREG不同，NRG 1未能支持缺乏肿瘤抑制因子Apc的致瘤前肠类器官的生长，Apc通常在人类结直肠癌（CRC）中突变。有趣的是，间质NRG 1的高表达与CRC队列中生存率的改善相关，表明了肿瘤抑制功能。我们的研究结果强调了间质NRG 1在转录重编程和保护肠上皮免受辐射损伤而不促进肿瘤发生中的作用。总结：参与再生反应的途径也可能促进肿瘤发生;然而，成纤维细胞衍生的EGF配体neuregulin 1保护肠上皮免受损伤，但不支持肿瘤生长。
Growth factors secreted by stromal fibroblasts regulate the intestinal epithelium. Stroma-derived epidermal growth factor (EGF) family ligands are implicated in epithelial regeneration and tumorigenesis, but their specific contributions and associated mechanisms remain unclear. Here, we use primary intestinal organoids modeling homeostatic, injured and tumorigenic epithelia to assess how the fibroblast-derived EGF family ligands neuregulin 1 (NRG1) and epiregulin (EREG) regulate the intestinal epithelium. NRG1 was expressed exclusively in the stroma, robustly increased crypt budding and protected intestinal epithelial organoids from radiation-induced damage. NRG1 also induced regenerative features in the epithelium, including a fetal-like transcriptome, suppression of the Lgr5+ stem cell pool and remodeling of the epithelial actin cytoskeleton. Intriguingly, unlike EGF and EREG, NRG1 failed to support the growth of pre-tumorigenic intestinal organoids lacking the tumor suppressor Apc, commonly mutated in human colorectal cancer (CRC). Interestingly, high expression of stromal NRG1 was associated with improved survival in CRC cohorts, suggesting a tumor-suppressive function. Our results highlight the power of stromal NRG1 in transcriptional reprogramming and protection of the intestinal epithelium from radiation injury without promoting tumorigenesis. Summary: Pathways involved in regenerative responses may also promote tumorigenesis; however, the fibroblast-derived EGF ligand neuregulin 1 protects the intestinal epithelium from injury, but does not support tumorigenic growth.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
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4.5
作者：
Mantilla Rojas C;McGill MP;Salvador AC;Bautz D;Threadgill DW
通讯作者：
Threadgill DW
影响因子：
12.4
作者：
Almohazey, Dana;Lo, Yuan-Hung;Frey, Mark R.
通讯作者：
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影响因子：
64.8
作者：
Ayyaz, Arshad;Kumar, Sandeep;Gregorieff, Alex
通讯作者：
Gregorieff, Alex
影响因子：
64.8
作者：
Gregorieff, Alex;Liu, Yu;Wrana, Jeffrey L.
通讯作者：
Wrana, Jeffrey L.