Wnt signalling maintains self-renewal of human hepatoblasts without blocking their differentiation

Hepatoblasts play a key role in liver organogenesis by differentiating into hepatocytes and cholangiocytes, the main functional cell types of the liver. Mouse studies have demonstrated an association of Wnt signalling with proliferation and differentiation of hepatoblasts. However, the exact function of this pathway in hepatic development has not been fully uncovered, especially in human. Here, we use hepatoblast organoids derived from human foetal livers to investigate the importance of Wnt signalling in self-renewal and cell fate decisions during liver development. We first showed that Wnt plays a key role in hepatoblast self-renewal capacity in vitro by maintaining their proliferative state. However, Wnt was not sufficient to block differentiation of hepatoblast organoids into hepatocytes or cholangiocytes, suggesting that other factors are necessary to maintain hepatoblast bipotency. Finally, single-cell transcriptomic analyses revealed that Wnt signalling activity correlates with hepatoblast proliferation in the human foetal liver, suggesting that the role for Wnt could be conserved in vivo. Taken together, our results support a model in which Wnt signalling acts to preserve the proliferative capacity of hepatoblasts without being sufficient to maintain their bipotent state.