Single‐cell and spatial transcriptomics reveal the fibrosis‐related immune landscape of biliary atresia

Chunjing Ye; Jiajie Zhu; Junfeng Wang; Deqian Chen; Lingdu Meng; Yong Zhan; Ran Yang; Shiwei He; Zifeng Li; Shuyang Dai; Yi Li; Song Sun; Zhen Shen; Yanlei Huang; Rui Dong; Gong Chen; Shan Zheng

doi:10.1002/ctm2.1070

Clinical and Translational Medicine (Nov 2022)

Single‐cell and spatial transcriptomics reveal the fibrosis‐related immune landscape of biliary atresia

Chunjing Ye,
Jiajie Zhu,
Junfeng Wang,
Deqian Chen,
Lingdu Meng,
Yong Zhan,
Ran Yang,
Shiwei He,
Zifeng Li,
Shuyang Dai,
Yi Li,
Song Sun,
Zhen Shen,
Yanlei Huang,
Rui Dong,
Gong Chen,
Shan Zheng

Affiliations

Chunjing Ye: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Jiajie Zhu: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Junfeng Wang: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Deqian Chen: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Lingdu Meng: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Yong Zhan: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Ran Yang: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Shiwei He: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Zifeng Li: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Shuyang Dai: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Yi Li: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Song Sun: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Zhen Shen: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Yanlei Huang: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Rui Dong: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Gong Chen: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina
Shan Zheng: Department of Pediatric SurgeryChildren's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal DiseaseMinistry of Health ShanghaiChina

DOI: https://doi.org/10.1002/ctm2.1070
Journal volume & issue: Vol. 12, no. 11
pp. n/a – n/a

Abstract

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Abstract Background Biliary atresia (BA) is a devastating inflammatory and fibrosing cholangiopathy of neonates with unknown aetiology. We aim to investigate the relationship between these two main characteristics. Methods Single‐cell RNA sequencing and spatial transcriptomics were performed on liver samples from a cohort of 14 objects (BA: n = 6; control: n = 8). We conducted data integration and cell‐type annotation based on gene expression profiling. Furthermore, we identified fibrosis‐related immune cells according to their spatial locations, GO and KEGG analysis. Finally, SPOTlight and CIBERSORTx were used to deconvolute ST data and microarray data of the GSE46960 cohorts, respectively. Results Immune subpopulations inhabiting the ‘fibrotic niche’ (areas of scarring), comprising ‘intermediate’ CD14++CD16+ monocytes, scar‐associated macrophages, natural killer T cells, transitional B cells and FCN3+ neutrophils were identified. GO and KEGG analyses showed that pathways including ‘positive regulation of smooth muscle cell/fibroblast proliferation’ and ‘positive regulation of/response to VEGFR/VEGF/EGFR/FGF’ were enriched in these cell types. Interactions analysis showed that communication among ‘FGF_FGFR’, ‘RPS19‐C5AR1’, ‘CD74_COPA/MIF/APP’ and ‘TNFRSF1A/B_GRN’ was extensive. Finally, the results of deconvolution for ST data and microarray data validated that the proportions of certain identified fibrosis‐related cell types we identified were increased in BA. Discussion Fibrosis is an important feature of BA, in which the immune system plays an important role. Our work reveals the subpopulations of immune cells enriched in the fibrotic niche of BA liver, as well as key related pathways and molecules; some are highlighted for the first time in liver fibrosis. These newly identified interactions might partly explain why the rate of liver fibrosis occurs much faster in BA than in other liver diseases. Conclusion Our study revealed the molecular, cellular and spatial immune microenvironment of the fibrotic niche of BA.

Published in Clinical and Translational Medicine

ISSN: 2001-1326 (Online)
Publisher: Wiley
Country of publisher: Australia
LCC subjects: Medicine: Medicine (General)
Website: https://onlinelibrary.wiley.com/journal/20011326

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