Yap as a master regulator of fibrosis

Liver fibrosis, cirrhosis, and liver cancer are an increasing problem worldwide but despite their high incidence and destructive outcomes, no efficient therapies are available. Importantly, fibrosis is not only a problem in the liver, but it can also affect other organs, such as the lung and kidney. Despite these devastating effects, current therapies for fibrosis and cirrhosis are not widely used in the clinic and they are limited to slowing escalation of the disease but cannot revert it. Liver fibrosis constitutes the deposition of excessive amounts of extra-cellular matrix (ECM), which is produced mostly by hepatic stellate cells (HSCs) that upon liver damage switch from a quiescent state to an activated myofibroblast-like state. Reversal of fibrosis is possible when the liver injury is stopped and aHSCs switch to a reverted state (rHSCs), this does not occur anymore when the disease has reached the cirrhotic stage. In this project we will investigate the molecular mechanisms that control fibrosis reversal and the switch of aHSCs into rHSCs. We will build on these findings and develop synthetic gene circuits that can trigger the reversal process in vivo. A molecular understanding of the reverted state of HSCs and the significance of the rHSCs for fibrosis reversal will fuel novel strategies to treat patients with irreversible liver cirrhosis.