GSE125688
Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration The liver is an essential organ with compartmentalized metabolic processes  and significant regenerative capabilities. Repopulation of the liver  parenchyma can transpire from both main epithelial cell types, hepatocytes  and biliary epithelial cells (BECs). Here, we harness high-throughput  single-cell RNA sequencing (scRNA-seq) to dissect the transcriptional  heterogeneity and cellular diversity of these epithelial compartments in  homeostasis and injury. Our data argue against the idea of a rigidly  defined liver progenitor cell in BECs, finding instead that heterogeneity  in homeostatic BECs is principally distinguished by a YAP-dependent  program that defines a dynamic cellular state. We report that this  cellular state dynamically fluctuates between BECs and can be induced in  the majority of BECs in response to environmental stimuli and injury.  Functional studies demonstrate that YAP is distinctly required for BEC  survival in homeostasis, uncovering a tight physiological necessity for  YAP signaling in BECs compared to other tissues. YAP is also essential for  hepatocyte reprogramming towards a ductal progenitor fate upon injury.  Finally, our data demonstrate that this YAP-driven cellular state is  highly responsive to injury by physiological exposure to bile acids (BAs)  via apical sodium-bile acid transporter, and that sequestration of  endogenous BAs rescues the cell loss phenotype associated with homeostatic  Yap deletion. Together, our findings uncover previously undescribed  molecular heterogeneity within the ductal epithelium and highlight a  distinct and potent role for YAP as a protective rheostat and regenerative  regulator in the mammalian liver. Overall design: RNA sequencing data from single biliary epithelial cells isolated from mouse livers