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

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.