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Abstract
Diseases of the bile duct (cholangiopathies) remain a common indication for liver transplantation, while little progress has been made over the last decade in understanding the underlying pathophysiology. This is largely due to lack of proper in vitro model systems to study cholangiopathies. Recently, a culture method has been developed that allows for expansion of human bile duct epithelial cells grown as extrahepatic cholangiocyte organoids (ncECOs) in non-canonical Wnt-stimulating conditions. These ncECOs closely resemble cholangiocytes in culture and have shown to efficiently repopulate collagen scaffolds that could act as functional biliary tissue in mice. Thus far, initiation of ncECOs required tissue samples, thereby limiting broad patient-specific applications. Here, we report that bile fluid, which can be less invasively obtained and with low risk for the patients, is an alternative source for culturing ncECOs. Further characterization showed that bile-derived cholangiocyte organoids (ncBCOs) are highly similar to ncECOs obtained from bile duct tissue biopsies. Compared to the previously reported bile-cholangiocyte organoids cultured in canonical Wnt-stimulation conditions, ncBCOs have superior function of cholangiocyte ion channels and are able to respond to secretin and somatostatin. In conclusion, bile is a new, less invasive, source for patient-derived cholangiocyte organoids and makes their regenerative medicine applications more safe and feasible.
Highlights
Cholangiopathies are associated with significant morbidity and mortality (Murray and Carithers, 2005; Levitsky, 2011)
We demonstrate that primary biliary epithelial cells collected from bile can be cultured and expanded efficiently in vitro while retaining their cholangiocyte characteristics
We show that these ncBCOs, could be efficiently initiated from endoscopic retrograde cholangiopancreatography (ERCP) and gallbladder bile and could be cultured long-term
Summary
Cholangiopathies are associated with significant morbidity and mortality (Murray and Carithers, 2005; Levitsky, 2011). A recent study published by Soroka et al (2019) showed feasibility of culturing cholangiocyte organoids from bile, obtained by ERCP The expansion of these bile-derived organoids were driven by canonical Wnt-signaling originally described for the growing intrahepatic cholangiocyte organoids (cICOs) (Huch et al, 2015). This canonical Wnt-signaling is stimulated by R-spondin, providing a cholangiocyte with a more stem celllike phenotype compared to in vivo cholangiocytes (Sato et al, 2009, 2011; Barker et al, 2010; Soroka et al, 2019; Rimland et al, 2020). The aim of this study is to initiate and expand non-canonical Wnt driven cholangiocyte organoids from bile (ncBCOs) and to compare these to canonical-Wnt driven bile cholangiocyte organoids (cBCOs) from the same bile samples and to ncECOs from (paired) bile duct tissue
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