Fate tracking reveals differences between Reelin(+) hepatic stellate cells (HSCs) and Desmin(+) HSCs in activation, migration and proliferation

The activation of hepatic stellate cells (HSCs) is the main cause of liver fibrogenesis in response to different etiologies of chronic liver injuries. HSCs are heterogeneous, but the lack of specific markers to distinguish different HSC subset hinders the development of targeted therapy for liver fibrosis. In this study, we aim to reveal new HSC subsets by cell fate tracking. We constructed a novel ReelinCreERT2 transgenic mouse model to track the fate of cells expressing Reelin and their progeny (Reelin(+) cells). And we investigated the property of Reelin(+) cells, such as differentiation and proliferation, in hepatotoxic (carbon tetrachloride; CCl(4)) or cholestatic (bile duct ligation; BDL) liver injury models by immunohistochemistry. Our study revealed that Reelin(+) cells were a new HSC subset. In terms of activation, migration, and proliferation, Reelin(+) HSCs displayed different properties from Desmin(+) HSCs (total HSCs) in cholestatic liver injury model but shared similar properties to total HSCs in hepatotoxic liver injury model. Besides, we did not find evidence that Reelin(+) HSCs transdifferentiated into hepatocytes or cholangiocytes through mesenchymal‐epithelial transition (MET). In this study, our genetic cell fate tracking data reveal that ReelinCreERT2‐labelled cells are a new HSC subset, which provides new insights into targeted therapy for liver fibrosis.