The liver is mainly constituted of hepatocytes, sinusoidal endothelial cells, stellate cells and macrophages called Kupffer cells (KCs). Together, these 4 cells represent 90% of all liver cells. Tissue-resident macrophages were long considered to only play a role in immune defense, but it is now clear that macrophages are essential for tissue homeostasis. Transcriptomic profiling has revealed that each tissue-resident macrophage expresses a unique gene expression profile. Little is known however about the precise cell-cell circuits that underlie the tissue-specific imprinting of macrophages. We hypothesize that the cell-cell circuits between the 4 main liver cells not only forms the blueprint of liver homeostasis, but that perturbations in these cell-cell interactions will lead to the development of liver diseases. Thus, the deLIVER-CRISPR project aims to elucidate how endothelial cells, stellate cells and hepatocytes imprint the KC identity, but also how, in turn, KCs influence the functional specialization of the other liver sinusoidal cells. We will use cutting-edge technologies, including CUT&RUN, snATAC-seq, in vivo CRISPR screens and spatial transcriptomics to unravel the key cell-cell interactions between these cells. Deciphering the reciprocal cell-cell interactions by which liver cells imprint the sinusoidal identity on one another in vivo is not only key to understand liver biology, it also paves the way for the development of in vitro liver organoids.