Location, location, location: a spatial perspective of liver heterogeneity in physiological and pathological contexts

Our study dissected liver heterogeneity in steady and ischemia-reperfusion (I/R) states based on spatial transcriptomics technique, from which we identified a novel therapeutic agent to alleviate I/R injury.
Location, location, location: a spatial perspective of liver heterogeneity in physiological and pathological contexts

Heterogeneity of physiological liver function

The hepatic lobule can be divided into the periportal zone (zone 1), the intermediary zone (zone 2), and the pericentral zone (zone 3) according to the direction of blood flow and oxygen supply1. Hepatocytes in different zones are functionally different. For example, zone 1 hepatocytes are enriched in oxygen supply and are involved in lipid β-oxidation and gluconeogenesis, zone 2 hepatocytes may play an essential role in hepatocyte regeneration, while zone 3 hepatocytes are mainly involved in lipid production, ketogenesis and glycolysis1. In addition, different hepatic non-parenchymal cells (NPCs) are also heterogeneously distributed along the periportal-pericentral axis and may be involved in liver zonation-related functions1,2. Our spatial transcriptomics study revealed that hepatic zone 1 is enriched with NPCs such as endothelial cells and hepatic stellate cells, which were reported to reduce inflammation, activate angiogenesis and serve as a backup to the hepatocytes3-5, we conjecture that NPCs enriched or activated in zone 1 may protect against certain adverse stimulus under pathological context, while zone 3-enriched hepatocytes may result in more active metabolism around the pericentral vein.


Zone-dependent I/R-induced liver injury

Liver is spatially heterogeneous in oxygen content, cell distribution and gene expression, causing zone-dependent liver injury patterns. Xenobiotics-induced zone-dependent liver injury due to toxic metabolites produced by the same zone-located enzymes. Non-alcoholic fatty liver disease exhibits a pericentral injury pattern due to active lipid synthesis in this zone6. Hepatic ischemia-reperfusion (I/R) injury, which is commonly observed during liver transplantation, has been reported to cause zone 3-specific injury with the underlying mechanisms remain unknown. In our hepatic I/R injury murine model, we observed a zone 3-specific injury pattern with histopathology. Therefore, we employed spatial transcriptomics to dissect molecular changes under the zone 3-dependent injury pattern, which showed an up-regulation of acute phase protein and heat shock protein genes in zone 3 post I/R accompanied by enriched injury-related pathways, such as response to unfolded protein, acute inflammatory response and autophagy. In addition, hepatic cell type heterogeneity and intercellular communication are essential in liver pathology7. We observed that Kupffer cells are enriched in zone 1,which may protect against liver I/R injury through the expression of heme oxygenase-18. Endothelial cells are enriched in zone 1 at steady state and significantly increase in proportion after I/R injury, suggesting enhanced angiogenesis and protection against post-I/R liver injury. We also observed enhanced infiltration of the pro-inflammatory M1-macrophages in zone 3, which may exacerbate liver injury by releasing cytokines and intercellular interactions.


Spatial transcriptomic-based drug repositioning

In order to identify small molecules that generate similar expression patterns of liver I/R and produce an ischemic pre-conditioning effect that may mitigate hepatic I/R injury, we queried the Connectivity MAP database with I/R-regulated and zone-dependent gene signatures, and the intersection of the candidates suggested that the small molecule celastrol may resolve I/R-induced liver injury through activating Hif1α pathway, which was further validated by experiment and suggest our approach efficient to predict potential therapeutics.


In summary, our study provides a spatial perspective of liver heterogeneity in physiological and pathological I/R injury contexts. A comprehensively understanding of tissue heterogeneity in terms of histopathology, molecular changes, and cell type dynamics  provide theoretical basis for therapeutic interventions.


Welcome to read our origin article (DOI: 10.1038/s42003-023-04564-0) in Communications Biology for more information and email us to discuss the topic.



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  8. Devey, L. et al. Tissue-resident macrophages protect the liver from ischemia reperfusion injury  via a heme oxygenase-1-dependent mechanism. Mol. Ther.17, 65-72 (2009). https://doi.org/10.1038/mt.2008.237.


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