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Updated: May 20, 2025
A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia
Published on: February 3, 2023
Scar-associated macrophages and biliary epithelial cells interaction exacerbates hepatic fibrosis in biliary atresia
Xin Li1,2, Tengfei Li1,3, Shaowen Liu1,3
1Graduate School, Tianjin Medical University, Tianjin, China.
Insights
Scar-associated macrophages (SAMs) drive biliary atresia (BA) fibrosis by promoting biliary epithelial cell (BEC) transition. New biomarkers identified may improve BA diagnosis and prognosis.
Area of Science:
- Hepatology
- Immunology
- Pediatric Gastroenterology
Background:
- Biliary atresia (BA) is a severe pediatric liver disease causing progressive bile duct obstruction and fibrosis.
- Current understanding of BA's liver microenvironment and fibrosis mechanisms remains incomplete.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms driving liver fibrosis in biliary atresia.
- To identify novel diagnostic biomarkers and therapeutic targets for BA.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on liver tissues from BA, choledochal cyst, and normal controls.
- Bioinformatic analysis to identify cell populations, gene signatures, and develop a diagnostic model.
Main Results:
- Identified scar-associated macrophages (SAMs) derived from monocytes as key drivers of fibrosis progression.
- Discovered SAMs promote epithelial-mesenchymal transition (EMT) in biliary epithelial cells (BECs).
- Upregulation of hub genes (CD96, EVL, S100A6, S100A11) in SAMs and regulatory T cells (Tregs) aids BA diagnosis.
Conclusions:
- SAMs and BECs exhibit pro-fibrotic phenotypes and co-localize in fibrotic areas, suggesting their interaction promotes EMT.
- Targeting SAM-BEC interactions presents a potential therapeutic strategy for biliary atresia.
- Identified biomarkers can enhance early diagnosis and predict postoperative prognosis in BA patients.
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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