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由TGF-β介导的细胞交叉驱动患者衍生的多隔间胆道器官中的表皮质-介质细胞过渡

Hiroaki Ayabe¹, Erica A K DePasquale², Surya P Amarachintha³

¹Department of Pediatrics, University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.

Nature communications

|July 17, 2025

概括

新生儿对胆道的敏感性与胆道发育受损有关. 在工程胆汁器官中抑制TGF-β信号改善了表皮细胞的发育,并减少了小鼠的疾病严重程度.

科学领域:

肝病学和发育生物学
儿科胃肠病学和肝病学
细胞和分子生物学是细胞和分子生物学.

背景情况:

新生儿疾病,包括胆管缩,源于上皮质结构和细胞成熟的发育缺陷.
胆管缩是一种严重的儿科胆管病变,影响胆管发育.
了解胆道发育对于解决新生儿对肝脏疾病的敏感性至关重要.

研究的目的:

研究人类胆道发育及其对胆道缩的脆弱性.
为研究胆汁发育而设计多部位胆汁器官 (MBOs).
探索TGF-β/Activin-SMAD2/3信号传递在胆道动中的作用.

主要方法:

人类肝脏衍生上皮质有机细胞与内皮细胞和介质细胞共同培养,以创建MBO.
来自正常和患病肝脏的MBO的比较,以确定发育缺陷.
在MBO中抑制TGF-β信号传递和胆道缩的小鼠模型.

主要成果:

正常的MBO复制了胆道表皮和周腺 (PBGs).
患病的MBO显示出缺陷的上皮层,上皮-介质细胞过渡 (EMT),并激活了TGF-β/Activin-SMAD2/3信号传导.
抑制TGF-β抑制了EMT,促进了MBOs中的胆道上皮的发育,并改善了小鼠的实验胆道动.

结论:

依赖TGF-β的EMT是胆道上皮细胞发育的关键调节剂.
调节TGF-β信号可以影响新生儿对胆道损伤的敏感性.
工程MBO为研究胆道发育和疾病提供了有价值的模型.

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相关概念视频

TGF - β Signaling Pathway

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...