Could endothelial TGFβ signaling be a promising new target for liver disease?

Chronic liver diseases are progressive and associated with increasing functional impairment as a consequence of organ fibrosis. While much effort has been directed at therapies that address underlying causes of disease such as hepatitis viruses or metabolic impairment in non-alcoholic fatty liver disease, effective treatments to prevent or reverse fibrogenesis have proven elusive and many patients die from the systemic complications of their cirrhosis despite successful management of the initiating disease. Persistent injury to the liver parenchyma drives hepatic fibrosis as part of a dysregulated repair response. This is characterized by expansion of activated myofibroblasts which perpetuate the inflammation and increase the production of extracellular matrix components such as collagen. While many of the myofibroblasts arise as a consequence of activation of hepatic stellate cells, migration of cells from other sources such as the portal fibroblasts, bone marrow, and mesenchymal transformation of epithelial and endothelial cells all contribute to the myofibroblast pool [Citation1]. Thus, there is much interest in identifying factors that govern the activation of myofibroblasts or matrix remodeling that could be targeted in a therapeutic context [Citation2]. The transforming growth factor beta (TGFβ) superfamily consists of multiple individual protein isoforms and plays a key role in many fibrotic diseases. Dysregulated TGFβ signaling underpins virtually all fibrotic diseases, but the specific mechanisms and intracellular responses are context dependent. Here, we consider a newly described contribution of TGFβ signaling in hepatic endothelial cells to consider whether this has potential as a therapy for fibrotic liver disease.