Description

Spatial Heterogeneity in Hepatocytes

Shani Ben-Moshe, Shalev Itzkovitz

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 7610001, Israel

The numerous metabolic and non-metabolic functions of the mammalian liver are carried out by hepatocytes in a region specific manner. The liver is composed of repeating units termed lobules, which are polarized by a directional blood flow from the portal nodes towards the central vein. This polarization creates gradients of oxygen, nutrients and hormones. Endothelial cells at the center of the lobule create an additional Wnt gradient. These gradients impose different microenvironments on the hepatocytes at each lobule zone. As a result, cells in different zones along the portocental axis are specialized for different metabolic functions, leading to spatial heterogeneity of the hepatocytes. A recent study in our lab performed spatially resolved single cell RNA seq on single hepatocytes, has shown that around half of the liver genes are zonated, with expression levels gradually increasing or decreasing from the central vein to the portal node, or even peaking in the mid-lobule zones.

We would like to further explore the yet unknown regulatory aspects of liver zonation. To this end, we plan to sort single hepatocytes from distinct zones, based on graded expression levels of zonated cell surface markers. Subsequently, we will perform intron-exon sequencing, as well as microRNA sequencing to each of the spatially resolved populations of sorted hepatocytes, to gain insight into the regulatory mechanisms of transcription and degradation controlling the gene expression patterns.

We further aim at characterizing the susceptibility of the hepatocytes to region specific damage, and the impact of the spatially biased damage on the DNA integrity, namely double strand breaks and mutations in the “damage zones”. Lastly, we will also explore the cell turnover dynamics in the different zones.

We believe that pursuing these goals will deepen our understanding of liver zonation and expose the processes that shape and maintain the zonation, and the zone-dependent predisposition to DNA damage.