Combating Chronic Liver Diseases via Understanding and Engineering Cell Competition and Fitness

Summary: Cell competition removes mutated cells and enables robust tissue development, eliminates oncogenic cells in adulthood, as well as damaged cells during aging. We identified activin A as an important player during cell competition, which we uncovered to be a major actor in liver repopulation by transplanted cells. We

showed that activin A is produced by hepatocytes and increased in aging liver. Highly proliferative fetal liver stem/progenitor cells exhibit reduced activin receptor expression, are resistant to activin A, and therefore have a growth advantage compared to mature hepatocytes. As a result, transplanted fetal liver cells are

capable to repopulate normal liver. In livers with advanced fibrosis, fetal liver cells differentiate into functional hepatic cells, effectively replace injured liver, and exhibit anti-fibrotic effects. Although fetal liver cells exhibit the capability to repopulate the liver, they will likely not be used for human cell transplantation.

Thus, we hypothesize that modulating hepatocytes or induced pluripotent stem cell-derived tissues to express crucial features of fetal liver cells will generate ‘winners’ capable of effectively restoring liver tissue mass. Generating a cell source with growth-advantage that is adapted to an injured microenvironment will

allow us to elucidate the mechanism of cell competition, which can be of invaluable therapeutic benefit. Here we first uncover the mechanism of cell competition in liver, using our rat cell transplantation model and modulated hepatocytes. Second, we will investigate the liver repair efficacy of competing human

hepatocytes – induced by blocking specifically activin A-signaling, using a small-molecule-based highly specific activin A antagonist – in diseased liver. Finally, we will use our recently developed human fetal liver organoids from induced pluripotent stem cells to produce liver progenitor cells with competitive advantage to

repopulate liver in vivo. Our studies will pave the path towards novel approaches for therapeutic cell transplantation in liver and application for a diverse set of liver diseases in human population.