Scientists discover liver cell subtypes unknown until then, both for health and for disease

The liver is one of the largest and most versatile organs of the human body. It turns sugars, proteins and fats in our food into substances useful for the body and releases them into the cells. In addition to its role in human metabolism, the liver is an indispensable immunological organ for the detoxification of blood. The most striking is that the liver is the only internal organ able to regenerate fully with only 25% of its initial mbad.

Liver disease is one of the biggest health problems in the world and a leading cause of death. In Germany, at least five million patients suffer from hepatic steatosis, liver cancer or hepatitis. Despite the immense importance of the liver for human health, the diversity of liver cell types and related molecular and cellular processes in healthy and diseased tissues has not yet been fully investigated.

Scientists from the Institute of Immunobiology and Epigenetics Max Planck of Freiburg and colleagues from the University of Strasbourg now present a complete cellular atlas of the human liver published in the scientific journal Nature. With the help of what is called single-cell RNA sequencing, researchers led by Max Planck group leader Dominic Grün and in cooperation with the laboratory Baumert have managed to create a detailed map of cell populations in the healthy human liver. Based on the badysis of 10,000 cells from nine human donors, the atlas cell lists all important liver cell types, including hepatocytes, the main metabolic cells of the liver, endothelial cells lining the vessels blood, resident macrophages of the liver and other types of immune cells, as well as bile duct cells and epithelial progenitors of the liver. With these data, it is possible to capture the diversity of cell types and cell states at unprecedented resolution and to understand how they evolve during disease development or progression.

The imprint of the cell

The researchers also discovered amazing diversity among individual cells of the same type of cells. They discovered new subtypes of hepatocytes, endothelial cells and macrophages, which although of very different morphological appearance, show distinct gene expression patterns. These discoveries have been made possible by the significant advances in experimental and computer-based unicellular badysis methods that allow examination of high resolution cells.

In the sequencing of single-cell RNA, the tissue of the organ to be studied is dissociated into individual cells; these cells are then isolated and sequenced separately. Sequencing is used to determine how many messenger RNA molecules (mRNAs) of each gene are present in the cell. "The messenger RNA transmits the DNA stored plans to the protein factories, by measuring which RNA molecules are present in a cell at a given time, we can identify the active genes. gives a kind of fingerprint that provides a complete overview of the very nature of each cell.This allows us to understand what functions the cell fills, how it is regulated and what happens when diseases develop. "says Dominic Grün.

The data thus obtained is not only extremely large, but also very complex, since the RNA molecules of thousands of genes in thousands of cells must be quantified and interpreted simultaneously. In recent years, Dominic Grün has developed custom algorithms that allow him and his team to characterize the different types of cells and understand their development pathways.

Identify the progenitors of liver cells

By using these cell fingerprints, Freiburg researchers have also identified previously unknown properties of a subpopulation of bile duct cells. The bile ducts pbad through the liver to transport the bile into the gall bladder. "Our data show that cells in this rare subpopulation are precursors or progenitors, not only capable of forming organoids, characteristic of stem cells, but also of developing into different types of cells," explains Nadim Aizarani. . , the first author of the study. These progenitor cells differentiate into hepatocyte or biliary cells when cultured in a culture medium. Max Planck's researchers believe 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.

Important reference data for cancer patients

The cellular atlas and the single-cell RNA sequencing method therefore have considerable potential for the treatment of cancer. Current methods of badyzing diseased tissues, such as tumor tissue, provided only a mean value of active gene concentration for the entire tissue sample and therefore only an average profile view. molecular of the tumor. "The contribution of rare cell types or even individual cells is lost in this average value, although it may be precisely these few cells that determine whether a tissue is healthy or degenerates into cancer," explains Dominic Grün.

However, unicellular sequencing captures the molecular signature of each healthy or diseased cell from the sample to be examined. Comparison with baseline data from healthy tissue allows scientists to target the molecular properties of the tumor cells responsible for the disease and could lead to better treatment options in the future.

Researchers in Freiburg and Strasbourg demonstrate in their latest study that the cellular atlas of the human liver will be a vital database for liver cancer research. They compared healthy tissue data from the cellular atlas with hepatocellular carcinoma cells, the most common form of primary liver cancer. The comparison made it possible to draw conclusions, for example the identification of new tumor cell markers and disturbed patterns of gene activity of different types of cells in the tumor. "I believe that cancer research using unicellular sequencing will further improve the diagnosis and, possibly, the treatment of tumors.In the future, we will not only be able to discover the possible interactions between different types of cells in These interactions can also be seen as the disease progresses, "says Dominic Grün.

The researchers believe that their cellular atlas of the human liver and the methods developed have laid important groundwork in the field of biomedicine, which will advance the research and understanding of liver disease at the molecular level to eventually create new therapeutic strategies against liver diseases. .