Title: Single-cell, single-nucleus, and spatial transcriptomics characterization of the immunological landscape in the healthy and PSC human liver
Background: Our limited understanding of PSC development remains a key barrier to discovering effective treatments. While specific immune cells have been implicated, their role in driving inflammation and disease progression is unclear. Prior studies have either analyzed isolated immune cells or whole liver tissue, failing to capture the complexity of these individual cells and in the liver microenvironment.
High-resolution single-cell maps are critically needed to examine the function of individual immune cells in liver health and disease.
Objective: Address a critical knowledge gap in understanding PSC disease progression by generating a comprehensive map of the PSC liver, comparing the activity, interactions, and locations of immune and non-immune cells in healthy versus PSC-affected livers.
Study Design:
- Researchers analyzed liver tissue from 10 PSC patients, 3 primary biliary cholangitis (PBC) patients, and 24 individuals with healthy livers. Over 47,000 individual cells from PSC/PBC livers and more than 100,000 from healthy livers were individually studied utilizing advanced single cell analysis techniques.
- This study used cutting-edge techniques to examine liver cells in PSC with unprecedented detail.
- Single-cell and single-nucleus RNA sequencing revealed gene activity across thousands of individual cells, while spatial transcriptomics mapped their locations within tissue.
- Findings were validated using flow cytometry, histology, and immunofluorescence to confirm cell types and functions.
Key Findings:
- Hepatocytes (liver cells) located near scar (fibrotic) tissue began to acquire features of cholangiocytes (bile duct cells)—a well-recognized phenomenon in liver diseases, especially evident in regions affected by PSC.
- These fibrotic areas in PSC livers demonstrated an active immune response.
- Macrophages, which normally support tissue repair, appeared dysfunctional in PSC.
- Previously unrecognized immune cell subtypes were discovered exclusively in PSC livers.
- Elevated signaling between immune and non-immune cells in PSC livers suggests targeted infiltration of immune cells into inflamed areas of the liver.
- A broad, coordinated inflammatory response appears to drive PSC progression, with multiple inflammation-related pathways highly active across immune and non-immune cells in the liver.
Impact for the PSC Community:
- The discovery of dysfunctional macrophages that contribute to maintaining liver inflammation highlights these cells as a potential target for novel therapies.
- By identifying specific cell types, their potential activities, and their locations within the diseased liver, this research helps provide a clearer picture of the underlying mechanisms driving PSC.
- Though centered on late-stage PSC, this study lays groundwork for exploring earlier disease stages and advancing more targeted, effective treatments.
