Authors
Xuelai Liu, Zhuo Liu, Huan Wang, Yuqiang Chen, Mao Ye, Xu Li, Yuanyuan Geng, Xiaoyun Cui, Feng He
Published in
Frontiers in pediatrics. Volume 14. Pages 1995199. Epub Oct 16, 2026.
Abstract
While immune dysfunction is recognized as pivotal in biliary atresia (BA) pathogenesis, comprehensive characterization of disease-specific immune cell subtypes and stromal components remains incomplete. This study aims to define the altered hepatic immune-stromal landscape and aberrant intercellular communication networks associated with BA progression using single-cell transcriptomics.
We performed single-cell RNA sequencing (scRNA-seq) on BA liver tissues to profile immune and stromal cell populations. Cellular subclustering, differential gene expression, pathway enrichment, and cell-cell communication analyses were employed to identify potential pathogenic drivers and predicted possible signaling networks. Multiplex immunofluorescence staining was used to verify receptor-ligand interaction in BA liver.
BA livers exhibited profound expansion of pro-inflammatory neutrophil subsets - Neutrophils with interferon-stimulated genes (Neu_ISG), Aged neutrophils (Neu_Aged) - with transcriptional signatures suggestive of enhanced reactive oxygen species (ROS) production, extracellular matrix (ECM) modulation, and cytokine activity. Concurrent cytotoxic/immunoregulatory lymphocyte populations - Effector memory CD4⁺ T Cell (CD4⁺ TEM), Tregs, cytotoxic NK cells- showed upregulated inflammatory and oxidative stress pathways. Periportal and lymphatic liver endothelial cells (LECs) demonstrated significant perturbations. Central venous LECs displayed signatures of oxidative stress and dysregulated proliferation/migration. Cell-cell communication analysis highlighted a possibly dominant "CXCL12-CXCR4" axis mediating neutrophil recruitment across endothelia, NK&T/B, and myeloid cells. Enhanced "MIF-CD74/CXCR4" signaling between endothelia and immune cells, "VEGFB-VEGFR1" interactions between hepatocyte-cholangiocyte compartments and central venous/periportal endothelia were observed, suggesting that these interactions are associated with BA progression.
Our scRNA-seq atlas uncovers coordinated innate/adaptive immune responses and endothelial-stromal dysfunction that shape a hepatic niche in BA associated with ROS, unchecked inflammation, and fibrotic remodeling. Key cellular and molecular contributors include pathogenic neutrophils, cytotoxic lymphocytes, and injured endothelia, which interact via "CXCL12-CXCR4" and "VEGFB-VEGFR1" signaling axes. These findings from the present exploratory study point to potential novel therapeutic targets (e.g., neutrophil subsets, chemokine pathways) for mitigating BA pathogenesis.
PMID:
42964246
Bibliographic data and abstract were imported from PubMed on 31 Oct 2026.
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