Liver diseases such as fatty liver disease, liver cancer, and hepatitis—to name a few—are a leading cause of death worldwide. Despite the immense importance of the liver for human health, a rising incidence of liver diseases, and limited treatment options, the diversity of cell types in the liver and their various molecular and cellular processes remain underappreciated.

Using single-cell RNA sequencing, researchers led by Dominic Grün, PhD, group leader at the Max Planck Institute of Immunobiology and Epigenetics have constructed a comprehensive cell atlas of the healthy human liver. Based on the analysis of 10,000 cells from nine human donors, the cell atlas maps all of the important liver cell types, including hepatocytes, the major metabolic cells of the liver, endothelial cells lining the blood vessels, liver resident macrophages and other immune cell types, as well as bile duct cells and liver epithelial progenitors.

The paper, “A human liver cell atlas reveals heterogeneity and epithelial progenitors,” published in Nature, details work done by a collaborative team from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the University of Strasbourg.


Single cells were isolated from liver tissue derived from nine different patients to perform single-cell RNA-sequencing. After applying computational single-cell analysis methods, a human liver cell atlas, or cell type map, was established, enabling the identification of previously unknown sub-types (depicted as clusters represented by numbers on the map). The researchers discovered rare sub-types of bile duct cells in the liver, which include a population of liver epithelial progenitors that can give rise to organoids capable of developing into hepatocytes or bile duct cells. [MPI of Immunobiology and Epigenetics, Freiburg, Grün]
In single-cell RNA sequencing, the organ tissue to be investigated is dissociated into individual cells; these cells are then isolated and sequenced separately. The sequencing is used to determine how many mRNA molecules of each gene are present in the cell. This method offers a kind of fingerprint that provides “a comprehensive insight into the very nature of each cell. This enables us to understand which functions the cell performs, how it is regulated, and also what happens when diseases develop,” explained Grün.

The researchers discovered an astonishing diversity among individual cells of the alleged same cell type. They found new subtypes of hepatocytes, endothelial cells, and macrophages, which, although hardly different in their morphological appearance, have discrete gene expression profiles.

The team also identified previously unknown properties of a subpopulation of bile duct cells. Bile ducts run through the entire liver to transport bile to the gallbladder. “Our data show that cells within this rare subpopulation are precursor cells or progenitors. They are not only able to form organoids, which is a marked characteristic of stem cells, but also have the potential to develop into different cell types,” explained Nadim Aizarani, a graduate student in the Grün lab and the first author of the study. These progenitor cells either differentiate into hepatocytes or bile duct cells when cultivated in a culture medium. The researchers hypothesize that this precursor cell population plays an important role in liver regeneration and could also be involved in the development of liver diseases or tumors. 

The cell atlas may also play a role in cancer therapy. Current approaches to analyze diseased tissue, such as tumor tissue, only provide an average value of the concentration of active genes for the entire tissue sample and thus only an average view of the tumor’s molecular profile. “The contribution of rare cell types or even individual cells is lost in this average value. Although it is perhaps precisely these few cells that determine whether a tissue is healthy or degenerates into cancer,” explained Grün. 

The researchers compared the data of healthy tissue from the cell atlas with cells from hepatocellular carcinoma, the most common form of primary liver cancer. The comparison enabled the identification of new tumor cell markers and perturbed gene activity patterns of different cell types within the tumor. “I think that research into cancer using single-cell sequencing will help to improve the diagnosis and eventually the treatment of tumors even further. In the future, we will not only be able to uncover possible interactions between different cell types in tumors but it will also be possible to observe these interactions as the disease progresses,” said Grün.

With these data, it is possible to capture the diversity of cell types and cell states at an unprecedented resolution and to understand how they change during development or upon disease progression. The atlas may advance the understanding of liver diseases on the molecular level to possibly create new therapeutic strategies against liver diseases in the future.

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