Cholestasis, which in severe cases could lead to liver failure, causes periportal damage on both hepatocytes and cholangiocytes. It is a long-term challenge to dissect regional pathogenesis of hepatocytes and cholangiocytes and the following regeneration in cholestasis. Here, we employed high resolution STEREO-seq and scRNA-seq to generate a spatiotemporal transcriptomic atlas of cholestatic injury. We found that cholangiocytes served as a signaling hub, associated with the lipid-associated macrophage (LAM) differentiation in periportal injury. In addition to excessive bile ductular reaction, our data identified that a subtype of liver progenitor-like cells (LPLC) near cholangiocytes showed an expression profile projecting to cholangiocytes, implying a conversion of cell identity. When dissecting regeneration, we found that extrinsic proliferative cues were already activated during cholestatic injury; however, inhibitory factor Atoh8 restricted hepatocyte proliferation. Only upon its downregulation in repair, hepatocyte proliferation was released. In summary, our study provides an essential resource for understanding regional liver injury and regeneration.
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