Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human

Abstract

The liver plays a critical role in both immune defense and tolerance in the body. The liver-resident immune cells (LrICs) determine the immune properties, but the unique composition and heterogeneity of these cells are incompletely understood. Here, we dissect the diversity of LrICs by a comprehensive transcriptomic profiling using the unbiased single-cell RNA-sequencing (scRNA-seq). A total of 70, 706 of CD45 + immune cells from the paired liver perfusion, spleen and peripheral blood as references were profiled. We identified more than 30 discrete cell populations comprising 13 of T and NK cell, 7 of B cell, 4 of plasma cell, and 8 of myeloid cell subsets in human liver and donorpaired spleen and blood, and characterized their tissue distribution, gene expression and functional modules. Especially, four of CXCR6 + T and NK cell subsets were found to be present preferentially in the liver, where they manifested heterogeneity, distinct function and prominent homeostatic proliferation. We propose a universal category system of T and NK cells based on distinct chemokine receptors, confirmed subsequently by phenotype, transcriptional factors and functionality. We also identified adaptive changes by the spleen and liver-derived monocyte and macrophage populations. Finally, we give a global glimpse on B cell and plasma cell subsets in human spleen and liver. We, therefore, reveal the heterogeneity and functional diversity of LrICs in human. This study presents comprehensively the landscape of LrICs and will enable further study on their roles in various human diseases.

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

“…In the human liver, hepatic macrophages consist of CD68 + MARCO + KCs, CD68 + MARCO − macrophages, and CD14 + monocytes. 16,17 CD68 + MARCO + KCs are characterized by enriched expression of genes involved in maintaining immune tolerance (e.g., VSIG4) and suppressing inflammation (e.g., CD163 and HMOX1). CD68 + MARCO − macrophages have a similar transcriptional profile (e.g., C1QC, IL-18, S100A8/9) as recruited proinflammatory macrophages.…”

“…16 However, both CD68 + MARCO − macrophages and hepatic CD14 + monocytes show significantly weaker proinflammatory responses than circulating CD14 + monocytes. 17 Functionality of hepatic macrophages during homeostasis KCs play a critical role in maintaining homeostasis of the liver and the whole body through five major functions. These include (i) clearance of cellular debris and metabolic waste, [18][19][20] (ii) maintenance of iron homeostasis via phagocytosis of red blood cells (RBCs) and the subsequent recycling of iron, [21][22][23][24] (iii) regulation of cholesterol homeostasis through the production of cholesteryl ester transfer protein, which is important for decreasing circulating high-density lipoprotein-cholesterol levels and increasing very low-density lipoprotein-cholesterol levels, 25 (iv) mediation of antimicrobial defense, 26,27 and (v) promotion of immunological tolerance.…”

Systemic Immunometabolism: Challenges and Opportunities

“…Recent advances in single-cell sequencing technology vastly expanded our understanding of cellular heterogeneity of organs and how this correlates with organ-specific immune responses and composition ( Aizarani et al., 2019 ; Han et al., 2020 ; Jaitin et al., 2019 ; Krausgruber et al., 2020 ; Stubbington et al., 2017 ; Zhao et al., 2020 ). For inter-organ coordination, mammals evolved blood, lymph, and nervous systems as communication channels ( Figure 1 B).…”

Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study

“…Since gene expression is regulated both at the transcriptional and epigenomic levels, the unprecedented power of carrying out concomitant and integrated analyses of scRNAseq and scATACseq data are increasingly evident. These new powerful tools have revealed the heterogeneity of cell types in the liver (Zhao et al, 2020), lungs (Domingo-Gonzalez et al, 2020), heart (Bykov et al, 2020), immune cells (Villani et al, 2017), and ECs (Kalluri et al, 2019;Kalucka et al, 2020) under various physiological and pathological conditions.…”