Cell atlas of CCl4-induced progressive liver fibrosis reveals stage-specific responses

Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis, a major cause of morbidity and mortality worldwide. There are no effective anti-fibrotic therapies available to date, which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cell-specific responses across different fibrosis stages. To reveal the multicellular networks regulating mammalian liver fibrosis from the mild to a severe phenotype, we have generated a single-nucleus transcriptomic atlas that encompasses 49,919 nuclei corresponding to different stages of murine carbon tetrachloride (CCl4)-induced progressive liver fibrosis. Integrative analysis distinguished the sequential responses in hepatocytes, hepatic stellate cells and endothelial cells. Moreover, we have reconstructed the cell–cell interactions and gene regulatory networks implicating in these processes. Altogether, these analyses have uncovered previously unnoticed mechanisms and/or stage-specific responses with potential clinical implications. Our dataset thus constitutes a relevant resource for understanding the molecular basis of progressive liver fibrosis.