The role of stem cells in liver repair and fibrosis.

In response to liver injury or loss of liver mass, proliferation of mature liver cells is the first-line defense to restore liver homeostasis. In the setting of chronic liver disease, however, the ability of hepatocytes and cholangiocytes to proliferate is blocked and small bipotential progenitor cells are activated. Recent studies have established the role of these facultative progenitor cells in injury repair and fibrosis in patients with chronic liver disease and in experimental models. Several signaling pathways linking progenitor cell activation and fibrosis have been identified, and there is increasing evidence that cross-talk (both physical and via soluble factors) between progenitor cells and myofibroblasts is essential for both fibrosis and parenchymal regeneration. Even more exciting are new data examining the cellular components of the progenitor cell niche, demonstrating that both resident liver cells and circulating cells from the bone marrow can function as stem cells, suggesting that there is a surprising degree of phenotypic plasticity such that progenitor cells can contribute to the myofibroblast population and vice versa. We highlight here recent findings from the literature demonstrating the cellular and functional complexity of the progenitor cell niche, and emphasize some of the important questions that remain to drive future research.