A non-catalytic function of a disintegrin and metalloprotease 10 determines hepatic progenitor cell fate

During chronic liver disease, hepatocytes may undergo proliferative arrest, leading to the activation, expansion and differentiation of hepatic progenitor cells (HPCs). Here we observe that expression of A Disintegrin And Metalloprotease (ADAM) 10 is increased in human and murine chronic liver disease correlating with HPC expansion. We report that proteolytic processing of ADAM10 by ADAM9 and generation of an ADAM10 intracellular domain that translocates to the nucleus, rather than ADAM10 enzymatic activity is essential for the regulation of HPC gene expression and differentiation. Genetic loss of ADAM10 in vitro and in vivo enhances stemness gene expression, increases the accumulation of undifferentiated HPCs and promotes the formation of liver fibrosis. Taken together, we demonstrate that a non-catalytic function of ADAM10 is an essential regulator of HPC fate and HPC-driven regeneration. Our data ascribe a non-proteolytic function to ADAM proteases which may be a general concept in adult tissue stem cells.