Liver fibrosis : Focus on myofibroblasts

Liver fibrogenesis is a dynamic process including quantitative and qualitative changes of the extracellular matrix, of which the most prominent is the deposition of type I collagen. These changes progressively disrupt normal liver architecture and result in cirrhosis formation. In the fibrotic liver, as in all other fibrotic tissues, the extracellular matrix is produced by myofibroblasts, which are characterized by the de novo expression of alpha-smooth muscle actin (alpha-SMA). Absent from the normal liver, myofibroblasts in the injured liver derive from two major sources: predominantly hepatic stellate cells (HSC), i.e. vitamin-A containing pericytes, and to a lesser extent portal mesenchymal cells, a heterogeneous population including vitamin-A free pericytes. Those derived from portal mesenchymal cells, known as portal myofibroblasts, distinguish themselves from HSC-derived myofibroblasts by clear phenotypic features but few, debated, markers the most discriminating so far being collagen-type-XV-alpha. Portal myofibroblasts appear to be critical in pathological angiogenesis, which constantly occurs in liver diseases, driving the progression of fibrosis from portal tracts towards the lobule to form cirrhosis. It has been clearly established that liver fibrosis and cirrhosis can regress, and this process involves a deactivation of CEF-derived myofibroblasts, although probably not to a fully quiescent phenotype. The proof of fibrosis reversibility in the liver provides a strong rationale for anti-fibrotic treatments none of which, nevertheless, has yet fully proven an effectiveness in liver diseases. The in vivo reprogramming of myofibroblasts in mouse liver into induced hepatocytes provides an innovative strategy for the future.