Hepatic stellate cells promote angiogenesis via the TGF-β1-Jagged1/VEGFA axis

Hepatic stellate cells (HSCs) are activated by transforming growth factor (TGF)-β1 and function as mesenchymal cells in liver regeneration. Activated HSCs also have proangiogenic ability in vivo. In this study, knockin of the TGF-β1 gene caused mHSCs to transform into myofibroblasts (MFs) highly expressing Jagged1 and vascular endothelial growth factor A (VEGFA). These MFs promoted formation of capillary-like structures by human umbilical vein endothelial cells (HUVECs) in vitro, which was much reduced after blocking TGF-β1 signaling. Transplantation of TGF-β1-knockin mHSCs was followed by efficient engraftment into livers and accompanied by increased vascular organization and expression of Jagged1 and VEGFA compared with controls. Less hepatic angiogenesis and lower Jagged1 and VEGFA expression, was found in livers engrafted with TGF-β-R1-knockdown mHSCs. Increased vascularization improved liver function. The findings showed that mHSCs were regulated by TGF-β1 signaling to express Jagged1 and VEGFA, which were associated with hepatic angiogenesis, a novel mechanism of mHSC promotion of new vascular structures.