Insights provided by single-cell approaches into the normal liver and the process of chronic liver disease. (IMAGE)
Caption
(A) scRNA-seq with ST can reveal spatial zonation profiles of gene expression in the normal liver and a detailed cell landscape of the human liver, showing that 50% of liver genes have partitioning rules. Intrahepatic resident immune cells are demonstrated their unique distribution and functions. The receptor tyrosine kinase Tie1 is the key to regulate vascular activity signals and liver regeneration. (B) The most important feature of the CHB process is immune dysregulation, with CD8+T at the center of the process; B cell reduction impairs specific T-cell subsets and decreases the clearance of HBV and the decreased cell population in hepatitis B samples results in poor IFN-α response but activated B-0 subpopulation. (C) TREM2+/CD9+macrophages and PDGFRα+collagen-producing myofibroblasts subpopulations involve in fibrosis process; ACKR1+ and PLVAP+ endothelial cells are found to accumulate in the fibrotic ecotone and participate in immune cell migration; Galectin-9 on Kupffer cells is associated with specific immunity and could be a potential therapeutic target for cirrhosis treatment. (D) ACLF samples show high expression of the genes FGF19, ADCY8, KRT17 and SPP1 secreted by macrophages resulting in reduced LVs and dysfunctional LyECs. The pro-inflammatory monocyte subtype THBS1 may reflect ACLF progression and poor prognosis. (E) HCC with different prognosis shows differential immune cell microenvironment changes, with increasing PD-1+/CD4+T & CD8+T cells and CD8+T diversity suggesting a good prognosis; high heterogeneity in HCC as well as the increasing subtypes of TAMs, exhausted CD8+T/Tregs, CD161+/CD8+T, CCL4+/PD-L1+/TAN, ILCs/ILC2a, CD24+/CD133+/EpCAM+/CD45- cells suggesting a poor prognosis. The Layilin gene is functionally associated with tumor-characteristic CD8+T cells and may serve as a new target for immunotherapy in HCC. ACLF, acute-on-chronic liver failure; ACKR1, atypical chemokine receptor 1; CHB, chronic hepatitis B; EpCAM, epithelial cell adhesion molecule; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IFN-α, interferon-α; LVs, lymphatic vessels; LyECs, lymphatic vessel endothelial cells; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; PDGFRα, recombinant human platelet-derived growth factor-α; PLVAP, plasmalemma vesicle-associated protein; scRNA-seq, single-cell transcriptome sequencing; SPP1, secretory phosphoprotein 1; ST, spatial transcriptome technology; TAMs, tumor-associated macrophages; TAN, tumors-associated neutrophil; THBS1, thrombospondin-1; Tie 1, tyrosine kinase with immunoglobulin like and EGF like domains 1; TREM2, triggering receptor expressed on myeloid cells-2.
Credit
Yusheng Jie, Bingliang Lin, Guanzi Chen, Wenli Xu
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CC BY-NC