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Spatial and Single-Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis
Jin-Zhong Li1, Liu Yang1, Min-Xi Xiao1
1Division of Infectious Disease, The First Affiliated Hospital of Jinan University, Guangzhou, China.
Summary
This study maps metabolic dysfunction-associated steatohepatitis (MASH) fibrosis in the liver, identifying key genes like ADAMTSL2 in myofibroblasts and revealing inflammation
Area of Science:
- Hepatology
- Molecular Biology
- Systems Biology
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by fat accumulation, inflammation, and fibrosis.
- Understanding the spatial distribution and cellular drivers of MASH-related liver fibrosis is crucial for developing targeted therapies.
Purpose of the Study:
- To map the regional distribution of MASH fibrosis within the liver using advanced spatial techniques.
- To identify specific cellular subpopulations and molecular targets associated with MASH fibrosis progression.
- To elucidate the temporal sequence of cellular events leading to MASH-induced liver fibrosis.
Main Methods:
- Spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) were employed to analyze liver tissues from healthy controls, simple steatosis, and MASH patients.
- Integration of spatial and scRNA-seq data identified fibrotic regions and associated cell types.
- Gene expression analysis pinpointed candidate genes (ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1, G6PC) within fibrotic clusters.
Main Results:
- Spatial transcriptomics revealed fibrotic regions predominantly in liver lobules.
- MASH livers showed increased inflammatory cells (Kupffer cells, T cells) and myofibroblasts.
- ADAMTSL2, PTGDS, and S100A6 expression correlated positively with fibrosis severity and distribution.
- ADAMTSL2+ myofibroblasts are implicated in TNF signaling and extracellular matrix production.
- Pseudotime analysis demonstrated that early MASH involves T cell and Kupffer cell infiltration, leading to HSC activation and fibrosis.
Conclusions:
- This study provides the first comprehensive characterization of lineage-specific gene expression, subpopulation dynamics, and temporal progression in MASH fibrosis.
- Identified genes and cellular pathways offer potential therapeutic targets for mitigating MASH-related liver fibrosis.
- The findings advance our understanding of MASH pathogenesis and highlight avenues for future drug development.
