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Scar-associated macrophages and biliary epithelial cells interaction exacerbates hepatic fibrosis in biliary atresia

Pediatric Research (2025)Cite this article

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Impact

  • 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.

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Fig. 1: Single-cell transcriptome profiles from a scRNA-seq cohort of livers.
Fig. 2: BECs exhibit EMT activation and pro-fibrotic phenotypes.
Fig. 3: Partial BECs have a tendency to differentiate towards HSCs.
Fig. 4: SAMs play a key role in liver fibrosis progression.
Fig. 5: SAMs are derived from monocytes and are associated with EMT activation.
Fig. 6: Interactions between fibrosis-associated cells, BECs, and HSCs.
Fig. 7: Construction of a novel fibrosis assessment model to aid BA clinical diagnosis and autologous liver survival prediction.
Fig. 8: Mechanism of the process of fibrosis in BA.

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Data availability

The data used and analyzed during the current study are available from Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/).

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Funding

This study was supported by grants from Tianshan Talent Training Program (Grant No. 2023TSYCJC0052), Tianjin Municipal Science& Technology Planning Project (Grant No. 21ZXGWSY00070), and Tianjin Applied Basic Research Project Planning Project (Grant No. 22JCZDJC00290).

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Author notes

  1. These authors contributed equally: Xin Li, Tengfei Li.

Authors and Affiliations

  1. Graduate School, Tianjin Medical University, Tianjin, China

    Xin Li, Tengfei Li, Shaowen Liu, Yilin Zhao, Yuqiang Chen, Qianhui Yang, Yu Meng, Jiaying Liu & Jiayinaxi Musha

  2. Department of General Surgery, Urumqi Children’s Hospital, Xinjiang, China

    Xin Li, Yuqiang Chen, Alimujiang Abudureyimu & Jiayinaxi Musha

  3. General Surgery Department, Tianjin Children’s Hospital, Tianjin, China

    Tengfei Li, Shaowen Liu, Yilin Zhao, Shujian Zhang, Liang Ge, Qianhui Yang, Yu Meng, Jiaying Liu & Jianghua Zhan

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Contributions

X.L. and T.F.L. designed the study and analyzed the data. T.F.L., S.W.L., L.G., S.J.Z., and Y.Q.C. collected the data. T.F.L., Q.H.Y., Y.M., J.Y.L., and J.M. drafted and revised the manuscript. T.F.L., Y.L.Z., and A.A. revised the images. T.F.L. and J.H.Z. revised the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Jianghua Zhan.

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The study was approved by the Ethics Committee of Tianjin Children’s Hospital (2022-SYYJCYJ-008) and informed consent was obtained from the legal guardian of each patient.

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Li, X., Li, T., Liu, S. et al. Scar-associated macrophages and biliary epithelial cells interaction exacerbates hepatic fibrosis in biliary atresia. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04100-2

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