Foxd1 expression identifies a distinct subset of hepatic stellate cells involved in liver fibrosis

Hepatic stellate cells (HSCs) are pericytes of the liver and are responsible for liver fibrosis and cirrhosis, which are end stages of chronic liver diseases. TFG-ß activates HSCs leading to differentiation of myofibroblasts in the process of liver fibrosis. While heterogeneity of HSCs is appreciated in the fibrotic liver, it remains elusive which HSC subsets mainly contribute to fibrosis. We here show that expression of pericyte marker, Foxd1, specifically marked a subset of HSCs in the Foxd1-fate tracer mice. HSCs fate-mapped by Foxd1 were preferentially localized in portal area and peripheral zone of normal liver and fibrotic liver induced by carbon tetrachloride. Furthermore, the deletion of Cbfß, which is necessary for TGF-ß signaling, in Foxd1-expressing cells ameliorated liver fibrosis. Thus, we identified an HSC subset which preferentially responds to liver injuries. Overall design: To examine the differences between tdTomato-positive and -negative hepatic stellate cells from Foxd1fm mice, RNA-seq was performed using untreated or carbon tetrachloride-treated mice (biological triplicates).