Heterogeneity and plasticity of cholangiocytes in liver injury: a journey from pathophysiology to therapeutic utility

Cholangiocytes are highly specialised cells participating in the pathobiology of various liver diseases and recognised to play a crucial role in response to liver injury. Cholangiocytes exhibit dramatic heterogeneity and plasticity, with distinct subtypes performing disparate functions during liver injury and regeneration. Acting as the liver progenitor cells, cholangiocytes can also convert to hepatocytes in the context of impaired hepatocyte proliferation. Harnessing the intrinsic regenerative ability of cholangiocytes is of great importance to alleviate liver injury and promote cholangiocyte-driven liver regeneration. Clinically, cholangiocytes and cholangiocyte organoids are expected to serve as favourable sources for cell therapy in cholangiopathies, which are known as a group of complex diseases involving the biliary system while lacking effective therapeutic options. A comprehensive understanding of the biological characteristics of cholangiocytes provides insights into developing cholangiocyte cell therapy for cholangiopathies. In this review, we discuss the critical role of cholangiocytes in liver injury and regeneration, reveal the underlying mechanism of cholangiocyte plasticity, and explore the prospects and challenges of using cholangiocytes as a source for cell therapy.