Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer‐Associated Fibroblasts Formed After Chronic Liver Injuries

Background and Aims Studies of the identity and pathophysiology of fibrogenic HSCs have been hampered by a lack of genetic tools that permit specific and inducible fate‐mapping of these cells in vivo . Here, by single‐cell RNA sequencing of nonparenchymal cells from mouse liver, we identified transcription factor 21 ( Tcf21 ) as a unique marker that restricted its expression to quiescent HSCs. Approach and Results Tracing Tcf21 + cells by Tcf21 ‐CreER (Cre‐Estrogen Receptor fusion protein under the control of Tcf21 gene promoter) targeted ~10% of all HSCs, most of which were located at periportal and pericentral zones. These HSCs were quiescent under steady state but became activated on injuries, generating 62%‐67% of all myofibroblasts in fibrotic livers and ~85% of all cancer‐associated fibroblasts (CAFs) in liver tumors. Conditional deletion of Transforming Growth Factor Beta Receptor 2 ( Tgfbr2 ) by Tcf21 ‐CreER blocked HSC activation, compromised liver fibrosis, and inhibited liver tumor progression. Conclusions In conclusion, Tcf21 ‐CreER–targeted perivenous stellate cells are the main source of myofibroblasts and CAFs in chronically injured livers. TGF‐β signaling links HSC activation to liver fibrosis and tumorigenesis.