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Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.

ABSTRACT: The liver is the largest solid organ in the body and is critical for metabolic and immune functions. However, little is known about the cells that make up the human liver and its immune microenvironment. Here we report a map of the cellular landscape of the human liver using single-cell RNA sequencing. We provide the transcriptional profiles of 8444 parenchymal and non-parenchymal cells obtained from the fractionation of fresh hepatic tissue from five human livers. Using gene expression patterns, flow cytometry, and immunohistochemical examinations, we identify 20 discrete cell populations of hepatocytes, endothelial cells, cholangiocytes, hepatic stellate cells, B cells, conventional and non-conventional T cells, NK-like cells, and distinct intrahepatic monocyte/macrophage populations. Together, our study presents a comprehensive view of the human liver at single-cell resolution that outlines the characteristics of resident cells in the liver, and in particular provides a map of the human hepatic immune microenvironment.

SUBMITTER: MacParland SA

PROVIDER: S-EPMC6197289 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.

MacParland Sonya A SA Liu Jeff C JC Ma Xue-Zhong XZ Innes Brendan T BT Bartczak Agata M AM Gage Blair K BK Manuel Justin J Khuu Nicholas N Echeverri Juan J Linares Ivan I Gupta Rahul R Cheng Michael L ML Liu Lewis Y LY Camat Damra D Chung Sai W SW Seliga Rebecca K RK Shao Zigong Z Lee Elizabeth E Ogawa Shinichiro S Ogawa Mina M Wilson Michael D MD Fish Jason E JE Selzner Markus M Ghanekar Anand A Grant David D Greig Paul P Sapisochin Gonzalo G Selzner Nazia N Winegarden Neil N Adeyi Oyedele O Keller Gordon G Bader Gary D GD McGilvray Ian D ID

Nature communications 20181022 1

The liver is the largest solid organ in the body and is critical for metabolic and immune functions. However, little is known about the cells that make up the human liver and its immune microenvironment. Here we report a map of the cellular landscape of the human liver using single-cell RNA sequencing. We provide the transcriptional profiles of 8444 parenchymal and non-parenchymal cells obtained from the fractionation of fresh hepatic tissue from five human livers. Using gene expression patterns ...[more]

PMID: 30348985

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Project description:Background & aimsThe multiple vital functions of the human liver are performed by highly specialised parenchymal and non-parenchymal cells organised in complex collaborative sinusoidal units. Although crucial for homeostasis, the cellular make-up of the human liver remains to be fully elucidated. Here, single-cell RNA-sequencing was used to unravel the heterogeneity of human liver cells, in particular of hepatocytes (HEPs) and hepatic stellate cells (HSCs).MethodThe transcriptome of ~25,000 freshly isolated human liver cells was profiled using droplet-based RNA-sequencing. Recently published data sets and RNA in situ hybridisation were integrated to validate and locate newly identified cell populations.ResultsIn total, 22 cell populations were annotated that reflected the heterogeneity of human parenchymal and non-parenchymal liver cells. More than 20,000 HEPs were ordered along the portocentral axis to confirm known, and reveal previously undescribed, zonated liver functions. The existence of 2 subpopulations of human HSCs with unique gene expression signatures and distinct intralobular localisation was revealed (i.e. portal and central vein-concentrated GPC3 + HSCs and perisinusoidally located DBH + HSCs). In particular, these data suggest that, although both subpopulations collaborate in the production and organisation of extracellular matrix, GPC3 + HSCs specifically express genes involved in the metabolism of glycosaminoglycans, whereas DBH + HSCs display a gene signature that is reminiscent of antigen-presenting cells.ConclusionsThis study highlights metabolic zonation as a key determinant of HEP transcriptomic heterogeneity and, for the first time, outlines the existence of heterogeneous HSC subpopulations in the human liver. These findings call for further research on the functional implications of liver cell heterogeneity in health and disease.Lay summaryThis study resolves the cellular landscape of the human liver in an unbiased manner and at high resolution to provide new insights into human liver cell biology. The results highlight the physiological heterogeneity of human hepatic stellate cells.

Project description:Purpose: The goals of this study were to identify cell specific expression patterns from a donor with a presumed diagnosis of autoimmune retinopathy (AIR). A particular focus of this study was to identify expression signatures of Müller glia and astrocytes in AIR. Methods: Independent libraries were prepared for foveal and peripheral retina from five human donors in two experiments. Foveal and peripheral samples in donors 1-3 were acquired, analyzed, and uploaded in a previous experiment (GSE130636). In donors 4-5, new reads were acquired from a 2-mm fovea-centered punch and an 8-mm peripheral punch from the inferotemporal region in each donor. Donor 4 had no documented history of retinal disease. Donor 5 was followed for 19 years at the University of Iowa Hospitals and Clinics for progressive visual field loss and pigmentary changes and was given a presumptive diagnosis of autoimmune retinopathy. Foveal and peripheral retinal tissue were gently dissociated in papain for 1.25 hours before cryopreservation. In both experiments, libraries were sequenced on a HiSeq4000. Sequenced reads were mapped to the human genome build hg19 with CellRanger(v3.0.1) and filtered to remove cells likely to be doublets or cells with a high proportion of mitochondrial reads. Libraries from all five donors were aggregated to the same effective sequencing depth, and log-normalization of aggregated reads was performed with Seurat (v2.3.4) using a scale factor of 10,000. Results: A total of 23,429 cells were recovered after filtering with 117,885,744 corresponding reads. A total of 9,801 cells were recovered from the fovea while 13,628 cells were recovered from the periphery. A total of 7,189 cells were recovered from the donor with presumed AIR. In total, 23 clusters were identified and corresponded to all retinal cell types. The proportion of recovered cells was compared between the control (donors 1-4) and AIR (donor 5) patients. In addition, differential expression analysis identified genes enriched in each population of cells originating from the AIR donor. Particular emphasis was given to the expression profiles of glial cells (Müller cells and astrocytes) that originated from the AIR donor. Conclusions: This study provides a complementary clinical and molecular interrogation of the retina in a blinding inflammatory condition. Glial cells from the AIR donor were enriched in genes implicated in reactive gliosis, including ANXA1. Clinical, histologic, and transcriptomic evidence identify the loss of cone and rod photoreceptor cells with relative preservation of inner retinal cell types.

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Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.

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Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.

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