The Multifaceted Role of Cholangiocytes in Neoplastic and Non-Neoplastic Cholangiopathies: From Bench to Bedside

Cholangiocytes represent one of the main endogenous liver cell populations. In the last decades, several studies demonstrated a highly dynamic range of cholangiocyte functions, including:

• Fetal Liver Development: primitive cholangiocytes of the ductal plate influence and drive hepatic arterial growth via HNF6, HNF1β, and VEGF-A. Recent studies hypothesized that congenital forms of biliary atresia and developmental cholangiopathies are related, and further highlighted clinical consequences of altered ductal plate and bile duct development in children and adults and potentially related therapeutic targets.

• Regulation of the Hepatic Immune Microenvironment: cholangiocytes can acquire antigen-presenting capabilities via cytokine-induced expression of class II antigen (MHCII), potentially contributing to their injury in immune-mediated cholangiopathies. While promising, cholangiocytes' pathogenetic and therapeutic consequences as an immune response regulator are yet to be fully explored.

• Liver Regeneration, Biliary Fibrosis, and Neoplastic Development: cholangiocytes and bile duct proliferation are pivotal for parenchymal regeneration in response to liver injury or surgical resection. However, cholangiocyte response and proliferation contribute to fibrosis and carcinogenesis in chronic diseases and are currently subjects of intense investigation.

• Bile secretion: The role of cholangiocytes' "secretome" and membrane transporters in cholestatic liver diseases and genetic cholangiopathies is increasingly explored. Furthermore, introducing bile acids-targeting drugs revolutionized this field and required a more granular evaluation of bile acids and gut-liver axis and their role in developing cholangiopathies and biliary fibrosis. Finally, the role of bile duct injury and cholangiopathies in cystic fibrosis are progressively detailed, while CFTR modulators used in clinical practice kindle the development of novel translational research fields.



This Research Topic will highlight recent advances in four main domains of cholangiocyte function: 1) liver development and related disease; 2) regulation of the immune microenvironment; 3) liver regeneration, biliary fibrosis, and neoplastic development; and 4) bile secretion. The goal is to provide a thorough and granular perspective on the innovative roles associated with cholangiocytes, discussing the most recent pre-clinical advancement and the clinical consequences these new perspectives can have on patient management. As pre-clinical models of cholangiocyte pathophysiology and related cholangiopathies are increasingly reported, innovative methodological approaches developed to answer clinically relevant questions are also a focus of this Research Topic.



The studies published in this Research Topic will highlight cholangiocytes' multifaceted role in liver pathophysiology and patient clinical management.

We welcome pre-clinical and clinical contributions in the form of original research, systematic and narrative review (including mini review), and methodological studies mainly related, but not limited, to the following fields:

• Developmental and Inherited Cholangiopathies (e.g., Biliary Atresia, Cystic Fibrosis, Alagille Syndrome, PFIC, HNF1β deficiency).

• Immune-mediated Cholangiopathies (e.g., Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, IgG4-associated cholangitis).

• Biliary Tract Cancer (e.g., Pathogenesis, Morphological and Molecular Profiles, and Therapeutic Targets).

• Biliary "secretome", related pathophysiological mechanisms and potential clinical applications.

Case reports will be evaluated and accepted if they present outstanding contributions to the current state-of-the-art. We particularly encourage submissions of studies with early-career investigators as first-authors.