Cell networks in the mouse liver during partial hepatectomy.

In solid tissues, homeostasis and post-injury regeneration involve a complex interplay among various cell types. The mammalian liver harbors numerous epithelial and non-epithelial cells, and the global signaling networks governing their interactions are unknown. To unravel the hepatic cell network, we purified 10 different cell populations from normal and regenerative mouse livers. Analyzing their transcriptomes unveiled ligand-receptor interactions and over 50,000 potential cell-cell interactions in both ground state and after partial hepatectomy. Importantly, about half of these differed between the two states, indicating massive changes in the cell network during regeneration. Our study provides the first comprehensive database of potential cell-cell interactions in liver cell homeostasis and regeneration. Leveraging this predictive model, we identified and validated two previously unknown signaling interactions involved in accelerating and delaying liver regeneration. Overall, we provide a novel platform for investigating autocrine/paracrine pathways in tissue regeneration, with broader applications to other complex multicellular systems.