A human liver cell atlas reveals heterogeneity and epithelial progenitors

Nature. 2019 Aug;572(7768):199-204. doi: 10.1038/s41586-019-1373-2. Epub 2019 Jul 10.

Abstract

The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM+ population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, Neoplasm / metabolism
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Cell Adhesion Molecules / metabolism
  • Chimera / immunology
  • Chimera / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / immunology
  • Epithelial Cells / cytology*
  • Epithelial Cells / immunology
  • Female
  • Gene Expression Regulation
  • Hepatocytes / cytology*
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Humans
  • Liver / cytology*
  • Liver / immunology
  • Male
  • Mice
  • Organoids / metabolism
  • RNA, Small Cytoplasmic / genetics
  • RNA-Seq
  • Reproducibility of Results
  • Stem Cells / cytology*
  • Stem Cells / immunology

Substances

  • Antigens, Neoplasm
  • Cell Adhesion Molecules
  • RNA, Small Cytoplasmic
  • TACSTD2 protein, human