Li Xin, Li Tengfei, Liu Shaowen, Zhao Yilin, Chen Yuqiang, Abudureyimu Alimujiang, Zhang Shujian, Ge Liang, Yang Qianhui, Meng Yu, Liu Jiaying, Musha Jiayinaxi, Zhan Jianghua
Graduate School, Tianjin Medical University, Tianjin, China.
Department of General Surgery, Urumqi Children's Hospital, Xinjiang, China.
Pediatr Res. 2025 May 18. doi: 10.1038/s41390-025-04100-2.
Biliary atresia (BA) is a severe pediatric biliary disorder characterized by the progressive obstruction of liver bile ducts. In the absence of treatment, fibrosis advances rapidly in most affected children. Despite the identification of various factors contributing to fibrosis progression, comprehensive investigations into the microenvironmental alterations within the liver are still scarce.
Single-cell RNA sequencing (scRNA-seq) was conducted on two normal tissues adjacent to liver tumors, two choledochal cyst liver tissues, and four BA liver tissues. This analysis, combined with spatial localization data, elucidated the heterogeneity of the livers affected by BA. Ultimately, a diagnostic model for BA was developed, leveraging high-resolution fibrosis-related gene signatures.
We identified scar-associated macrophages (SAMs) originating from monocytes, which played a pivotal role in fibrosis progression and may be implicated in the epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs). Furthermore, the hub genes CD96, EVL, S100A6, and S100A11 were found to be upregulated in SAMs and regulatory T cells (Tregs), aiding in the diagnosis of BA.
SAMs and BECs not only exhibited a pro-fibrotic phenotype but also co-localized within fibrotic regions. Their interaction may facilitate the activation of EMT, highlighting a potential therapeutic target for BA treatment.
Analysis of the immune landscape: Through single-cell and spatial transcriptomic techniques, the paper reveals the complex immune landscape associated with BA fibrosis. Exploration of new therapeutic targets: This paper reveals that SAMs can promote the progression of liver fibrosis by regulating the EMT conversion of BECs, opening up a new therapeutic approach. Application of diagnostic markers: The paper identifies biomarkers that may improve early diagnostic accuracy and postoperative prognosis and recommends their incorporation into clinical practice.
胆道闭锁（BA）是一种严重的儿科胆道疾病，其特征为肝内胆管进行性梗阻。若不进行治疗，大多数患病儿童的纤维化会迅速进展。尽管已确定多种促成纤维化进展的因素，但对肝脏内微环境改变的全面研究仍很匮乏。
对两块肝肿瘤旁正常组织、两块胆总管囊肿肝组织和四块BA肝组织进行了单细胞RNA测序（scRNA-seq）。该分析结合空间定位数据，阐明了受BA影响的肝脏的异质性。最终，利用高分辨率纤维化相关基因特征建立了BA诊断模型。
我们鉴定出源自单核细胞的瘢痕相关巨噬细胞（SAMs），其在纤维化进展中起关键作用，可能与胆管上皮细胞（BECs）的上皮-间质转化（EMT）有关。此外，发现关键基因CD96、EVL、S100A6和S100A11在SAMs和调节性T细胞（Tregs）中上调，有助于BA的诊断。
SAMs和BECs不仅表现出促纤维化表型，还在纤维化区域共定位。它们的相互作用可能促进EMT的激活，突出了BA治疗的潜在靶点。
免疫格局分析：通过单细胞和空间转录组技术，本文揭示了与BA纤维化相关的复杂免疫格局。新治疗靶点探索：本文揭示SAMs可通过调节BECs的EMT转化促进肝纤维化进展，开辟了新的治疗途径。诊断标志物应用：本文鉴定出可能提高早期诊断准确性和术后预后的生物标志物，并建议将其纳入临床实践。
