Mapping the Liver: A New Look Inside Healthy and Fibrotic Human Livers at Single-Cell Resolution

Image credit: https://openai.com/index/dall-e/

The liver is a vital organ, responsible for many essential functions in the body. Scientists have long been studying the different types of cells that make up the liver and how they are organized. New research using advanced techniques is now providing a much clearer picture of this complex organ.

What's new?

This new study combines two powerful methods, called MERFISH and snRNA-seq, to create a detailed map of the liver at the single-cell level. This means they can see exactly where different types of cells are located and what genes they are using. Think of it like having a super-powered GPS for the liver.

• MERFISH (multiplexed error robust fluorescence in situ hybridization) is like a special microscope that can identify specific RNA molecules (the instructions for making proteins) within individual cells. It allows scientists to see the spatial arrangement of cells in the liver.
• snRNA-seq (single-nucleus RNA sequencing) looks at the RNA found inside the nuclei of cells. This gives a more comprehensive view of the genes being used by different cell types.

By combining these methods, the researchers have been able to identify different types of cells and how they function within the liver, in both healthy and diseased tissue.

The liver's inner structure

The liver is made up of tiny structures called lobules. Within these lobules, liver cells, known as hepatocytes, are traditionally thought to be arranged into three zones:

• Zone 1: Nearest to the blood supply. These hepatocytes are more involved in processes like making glucose and breaking down fatty acids.
• Zone 3: Furthest from the blood supply. These hepatocytes are more active in glucose breakdown and making fats.
• Zone 2: In between zones 1 and 3.

However, this study suggests that these zones may not be strictly separated, and that the gene expression in hepatocytes changes more gradually, reflecting a continuum from the portal to central regions of the lobule. The researchers observed different gene expressions in different areas: SDS, CYP2A6, ASS1 are enriched in portal regions. CYP2E1 and GLUL are enriched in central regions and ALDOB and ADH1B are enriched in zone 2.

Beyond hepatocytes, the liver also contains other important cells, including:

• Hepatic stellate cells (HSCs): Which have different sub-populations found across the liver.
• Macrophages: Immune cells that clear up debris. These are also found in sub-populations, with one type, Kupffer cells, scattered throughout the lobule, and another type more enriched in the portal area.
• Endothelial cells (ECs): Cells that line the blood vessels.
• Cholangiocytes: Cells lining the bile ducts.

Cell communication

The scientists also looked at how different cells in the liver communicate with each other by analyzing receptor-ligand interactions. They found that the location of hepatocytes influences how they interact with other cells. For example:

• Periportal hepatocytes (zone 1) interact with macrophages via the TGFB3-TGFBR1 pathway and with HSCs and ECs through PLA2G2A signaling.
• Pericentral hepatocytes (zone 3) communicate with HSCs and macrophages through GDF7 and TENM3/TENM2 signaling.

This detailed map of cell communication offers vital insights into how the liver functions and may help with the development of new therapies for liver diseases.

What about liver disease?

The study also examined liver samples from people with fibrosis, a condition where the liver becomes scarred due to long-term injury. They found that:

• While some hepatocytes in the fibrotic liver maintained their original zonal locations, two new types of hepatocytes emerged that did not follow this zonal pattern.
• These new hepatocyte populations showed different gene expressions, especially in pathways related to metabolism and the urea cycle.
• Macrophages in fibrotic livers showed a loss of markers associated with Kupffer cells and exhibited a gene expression profile more akin to a different population of macrophages found in the healthy liver.

Key Takeaways

This research provides us with a detailed spatial understanding of the liver, revealing first, a new view of liver zonation, suggesting it's more of a gradient than distinct zones. Second, specific locations of different cell types and how they interact within the liver lobule and third, changes in liver cells and their gene expression during liver injury, including the emergence of new hepatocyte populations that do not follow zonal patterns. The information may be useful in developing new treatments for liver disease. This new research is a big step forward in our understanding of the liver, highlighting the importance of not only knowing what cell types are present but also where they are located and how they interact.

 

Additional information: Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution. Nature communications (2024). https://doi.org/10.1038/s41467-024-55325-4

Journal information: https://www.nature.com/ncomms/