Genetic Targeting Of Hepatocytes Subpopulations In Hepatic Lobules And Organ-Specific Blood Vessels

Hepatocytes are functionally heterogeneous and are divided into two distinct populations based on their metabolic zonation:the periportal and pericentral hepatocytes.Here we show that Mfsd2a(Major facilitator superfamily domain-containing protein 2)is a periportal zonation marker and Cyp2e1(Cytochrome P450 2E1)is a pericentral zonation marker.By genetic lineage tracing of Mfsd2a~+periportal hepatocytes,we show that Mfsd2a~+hepatocytes decreased during liver homeostasis and expands to replace the pericentral hepatocyte population during chronic liver injury.After injury recovery,the Mfsd2a~+derived hepatocytes were reprogrammed into pericentral hepatocytes to re-establishes the metabolic zonation.By genetic lineage tracing of Cyp2e1~+pericentral hepatocytes,we show that Cyp2e1~+hepatocytes almost disappeared during chronic liver injury.Hepatocytes are heterogeneous,and different hepatocytes respond differently to injury.Using dual homologous recombinase,we establish a genetic system that target periportal and pericentral hepatocytes simultaneously to study the response of different hepatocytes to injury stimuli.Vascular networks supply oxygen and nutrients to organs to maintain physiological function of organs.The blood vessels of different organs are structurally and functionally heterogeneous.To more precisely dissect their distinct in vivo function in individual organs,we took advantage of two orthogonal recombination systems to create a genetic targeting system that targets vascular endothelial cells in an organ-specific manner.Applying this new system,we generated a coronary endothelial cell specific Cre(Co EC-Cre)and a brain endothelial cell specific Cre(BEC-Cre).By deletion of VEGFR2 using BEC-Cre,we showed that VEGF signaling regulates angiogenesis and the integrity of the blood-brain barrier in the central nervous system.